Protein structure is dynamic: the intrinsic flexibility of polypeptides facilitates a range of conformational fluctuations, and individual protein chains can assemble into complexes. Proteins are also dynamic in evolution: significant variations in secondary, tertiary and quaternary structure can be observed among divergent members of a protein family. Recent work has highlighted intriguing similarities between these structural and evolutionary dynamics occurring at various levels. Here we review evidence showing how evolutionary changes in protein sequence and structure (...) are often closely related to local protein flexibility and disorder, large‐scale motions and quaternary structure assembly. We suggest that these correspondences can be largely explained by neutral evolution, while deviations between structural and evolutionary dynamics can provide valuable functional insights. Finally, we address future prospects for the field and practical applications that arise from a deeper understanding of the intimate relationship between protein structure, dynamics, function and evolution. (shrink)

The SARS‐CoV‐2 virus is responsible for the COVID‐19 pandemic the world experience since 2019. The protein responsible for the first steps of cell invasion, the spike protein, has probably received the most attention in light of its central role during infection. Computational approaches are among the tools employed by the scientific community in the enormous effort to study this new affliction. One of these methods, namely molecular dynamics (MD), has been used to characterize the function of the (...) spike protein at the atomic level and unveil its structural features from a dynamic perspective. In this review, we focus on these main findings, including spike protein flexibility, rare S protein conformational changes, cryptic epitopes, the role of glycans, drug repurposing, and the effect of spike protein variants. (shrink)

A general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle,” required for function is proposed. It is suggested that the free‐energy landscape of a protein is biased toward this conformational cycle. Fluctuations into higher energy, although thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intraprotein interactions that contribute most to the free‐energy landscape. Some network connections are consistent in (...) every structural state, while others periodically change their interaction strength according to the conformational cycle. It is reviewed here that structural transitions change these periodic network connections, which then predisposes the protein toward the next set of network changes, and hence the next structural change. These concepts are illustrated by recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states. (shrink)

Intermediate filaments, which form the structural framework of both the cytoskeleton and the nuclear lamina in most eukaryotic cells, have been found to be highly dynamic structures. A continuous exchange of subunit proteins at the filament surface and a stabilisation of soluble subunits by chaperone‐type proteins may modulate filament structure and plasticity. Recent studies on the cell cycle‐dependent interaction of intermediate filaments with associated proteins, and a detailed analysis of intermediate filament phosphorylation in defined subcellular locations at various stages of (...) mitosis, have brought new insights into the molecular mechanisms involved in the mitotic reorganisation of intermediate filaments. Some of these studies have allowed new speculations about the possible cellular functions of cytoplasmic intermediate filaments, and increased our understanding of the specific functions of the lamins and the lamina‐associated membrane proteins in the post‐mitotic reassembly of the nucleus. (shrink)

The study of intrinsic phosphorylation dynamics and kinetics in the context of complex protein architecture in vivo has been challenging: Method limitations have prevented significant advances in the understanding of the highly variable turnover of phosphate groups, synergy, and cooperativity between P‐sites. However, over the last decade, powerful analytical technologies have been developed to determine the full catalog of the phosphoproteome for many species. The curated databases of phospho sites found by mass spectrometry analysis and the computationally predicted (...) sites based on the linear sequence of kinase motifs are valuable tools. They allow investigation of the complexity of phosphorylation in vivo, albeit with strong discrepancies between different methods. A series of hypothetical scenarios on combinatorial processive phosphorylation is proposed that are likely unverifiable with current methodologies. These proposed a priori postulates could be considered as possible extensions of the known schemes of the activation/inhibition signaling process in vivo. (shrink)

In this paper, a mathematical model was used to evaluate a dynamical hybrid system for optimizing and controlling the efficacy of plant-based protein in aquafeeds. Fishmeal, raw rapeseed meal, and a fermented meal with yeast and fungi were used as test ingredients for the determination of apparent digestibility coefficients of dry matter, crude protein, crude lipid, energy, and essential amino acids for olive flounder using diets containing 0.5% Cr2O3 as an inert indicator. Among all ingredients tested, FM had (...) the maximum ADC of dry matter, and energy. Fermented meals showed higher ADC. Amino acid digestibility reflects protein digestibility in most cases. Interestingly, protease, lipase, and amylase activities were better expressed in RM-Koji, RM-Yeast, and FM over RM, respectively. The current results deliver important information on nutrients and energy bioavailability in raw and fermented RM, which can be implemented to accurately formulate applied feeds for olive flounder. Compared with other applicable systems, the complexity of the approach implemented has been considerably reduced. (shrink)

Cyclic adenosine monophosphate (cAMP) and cAMP‐dependent protein kinase A (PKA) are evolutionary conserved molecules with a well‐established position in the complex network of signal transduction pathways. cAMP/PKA‐mediated signaling pathways are implicated in many biological processes that cooperate in organ development including the motility, survival, proliferation and differentiation of epithelial cells. Cell surface polarity, here defined as the anisotropic organisation of cellular membranes, is a critical parameter for most of these processes. Changes in the activity of cAMP/PKA elicit a variety (...) of effects on intracellular membrane dynamics, including membrane sorting and trafficking. One of the most intriguing aspects of cAMP/PKA signaling is its evolutionary conserved abundance on the one hand and its precise spatial–temporal actions on the other. Here, we review recent developments with regard to the role of cAMP/PKA in the regulation of intracellular membrane trafficking in relation to the dynamics of epithelial surface domains. BioEssays 30:146–155, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Conformational changes of proteins and other biomolecules play a fundamental role in their functional mechanism. Single pair Förster resonance energy transfer offers the possibility to detect these conformational changes and dynamics, and to characterize their underlying kinetics. Using spFRET on microscopes with different modes of detection, dynamic timescales ranging from nanoseconds to seconds can be quantified. Confocal microscopy can be used as a means to analyze dynamics in the range of nanoseconds to milliseconds, while total internal reflection fluorescence (...) microscopy offers information about conformational changes on timescales of milliseconds to seconds. While the existence of dynamics can be directly inferred from the FRET efficiency time trace or the correlation of FRET efficiency and fluorescence lifetime, additional computational approaches are required to extract the kinetic rates of these dynamics, a short overview of which is given in this review. The functional mechanism of proteins is often driven by underlying conformational changes. These intramolecular changes and dynamics can be investigated using single pair Förster resonance energy transfer. The kinetic timescales of the dynamics in the range of nanoseconds to seconds is then quantified using different experimental and analytical implementations. (shrink)

How do common and rare genetic polymorphisms contribute to quantitative traits or disease risk and progression? Multiple human traits have been extensively characterized at the genomic level, revealing their complex genetic architecture. However, it is difficult to resolve the mechanisms by which specific variants contribute to a phenotype. Recently, analyses of variant effects on molecular traits have uncovered intermediate mechanisms that link sequence variation to phenotypic changes. Yet, these methods only capture a fraction of genetic contributions to phenotype. Here, in (...) reviewing the field, it is proposed that complex traits can be understood by characterizing the dynamics of biochemical networks within living cells, and that the effects of genetic variation can be captured on these networks by using protein–protein interaction (PPI) methodologies. This synergy between PPI methodologies and the genetics of complex traits opens new avenues to investigate the molecular etiology of human diseases and to facilitate their prevention or treatment. (shrink)

Phosphatidylinositol 3‐phosphate (PtdIns3P) is generated on the cytosolic leaflet of cellular membranes, primarily by phosphorylation of phosphatidylinositol by class II and class III phosphatidylinositol 3‐kinases. The bulk of this lipid is found on the limiting and intraluminal membranes of endosomes, but it can also be detected in domains of phagosomes, autophagosome precursors, cytokinetic bridges, the plasma membrane and the nucleus. PtdIns3P controls cellular functions through recruitment of specific protein effectors, many of which contain FYVE or PX domains. Cellular processes (...) known to be controlled by PtdIns3P and its effectors include endosomal fusion, sorting and motility, autophagy, cytokinesis, regulated exocytosis and signal transduction. Here we discuss how Ptdins3P is generated on specific cellular membranes, how its localizations and functions can be studied, and how its effectors serve to control cellular functions.Editor's suggested further reading in BioEssays:Phosphatidylinositol 4,5‐bisphosphate: Targeted production and signaling AbstractHow does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity? AbstractPhosphatidylinositol‐3,4,5‐trisphosphate: Tool of choice for class I PI 3‐kinases AbstractPhosphatidylinositol‐4‐phosphate: The Golgi and beyond Abstract. (shrink)

Outer membrane proteins (OMPs) maintain the viability of Gram‐negative bacteria by functioning as receptors, transporters, ion channels, lipases, and porins. Folding and assembly of OMPs involves synchronized action of chaperones and multi‐protein machineries which escort the highly hydrophobic polypeptides to their target outer membrane in a folding competent state. Previous studies have identified proteins and their involvement along the OMP biogenesis pathway. Yet, the mechanisms of action and the intriguing ability of all these molecular machines to work without the (...) typical cellular energy source of ATP, but solely based on thermodynamic principles, are still not well understood. Here, we highlight how different single‐molecule studies can shed additional light on the mechanisms and kinetics of OMP biogenesis. (shrink)

Replication protein A (RPA), the major single‐stranded DNA‐binding protein in eukaryotic cells, is required for processing of single‐stranded DNA (ssDNA) intermediates found in replication, repair, and recombination. Recent studies have shown that RPA binding to ssDNA is highly dynamic and that more than high‐affinity binding is needed for function. Analysis of DNA binding mutants identified forms of RPA with reduced affinity for ssDNA that are fully active, and other mutants with higher affinity that are inactive. Single molecule studies (...) showed that while RPA binds ssDNA with high affinity, the RPA complex can rapidly diffuse along ssDNA and be displaced by other proteins that act on ssDNA. Finally, dynamic DNA binding allows RPA to prevent error‐prone repair of double‐stranded breaks and promote error‐free repair. Together, these findings suggest a new paradigm where RPA acts as a first responder at sites with ssDNA, thereby actively coordinating DNA repair and DNA synthesis. (shrink)

Targeted transitions in chromatin states at thousands of genes are essential drivers of eukaryotic development. Therefore, understanding the in vivo dynamics of epigenetic regulators is crucial for deciphering the mechanisms underpinning cell fate decisions. This review illustrates how, in addition to its cell memory function, the Polycomb group of transcriptional regulators orchestrates temporal, cell and tissue‐specific expression of master genes during development. These highly sophisticated developmental transitions are dependent on the context‐ and tissue‐specific assembly of the different types of (...) Polycomb Group (PcG) complexes, which regulates their targeting and/or activities on chromatin. Here, an overview is provided of how PcG complexes function at multiple scales to regulate transcription, local chromatin environment, and higher order structures that support normal differentiation and are perturbed in tumorigenesis. (shrink)

Although the importance of weak protein‐protein interactions has been understood since the 1980s, scant attention has been paid to this “quinary structure”. The transient nature of quinary structure facilitates dynamic sub‐cellular organization through loose grouping of proteins with multiple binding partners. Despite our growing appreciation of the quinary structure paradigm in cell biology, we do not yet understand how the many forces inside the cell – the excluded volume effect, the “stickiness” of the cytoplasm, and hydrodynamic interactions – (...) perturb the weakest functional protein interactions. We discuss the unresolved problem of how the forces in the cell modulate quinary structure, and to what extent the cell has evolved to exert control over the weakest biomolecular interactions. We conclude by highlighting the new experimental and computational tools coming on‐line for in vivo studies, which are a critical next step if we are to understand quinary structure in its native environment. (shrink)

The discovery and engineering of novel fluorescent proteins (FPs) from diverse organisms is yielding fluorophores with exceptional characteristics for live‐cell imaging. In particular, the development of FPs for fluorescence (or Förster) resonance energy transfer (FRET) microscopy is providing important tools for monitoring dynamic protein interactions inside living cells. The increased interest in FRET microscopy has driven the development of many different methods to measure FRET. However, the interpretation of FRET measurements is complicated by several factors including the high fluorescence (...) background, the potential for photoconversion artifacts and the relatively low dynamic range afforded by this technique. Here, we describe the advantages and disadvantages of four methods commonly used in FRET microscopy. We then discuss the selection of FPs for the different FRET methods, identifying the most useful FP candidates for FRET microscopy. The recent success in expanding the FP color palette offers the opportunity to explore new FRET pairs. (shrink)

An interplay between DNA‐dependent biological processes appears to be crucial for cell viability. At the molecular level, this interplay relies heavily on the communication between DNA‐bound proteins, which can be facilitated and controlled by the dynamic structure of double‐stranded DNA. Hence, DNA structural alterations are recognized as potential tools to transfer biological information over some distance within a genome. Until recently, however, direct evidence for DNA structural information as a mediator between cellular processes was lacking. This changed when the concept (...) of transient waves of DNA supercoiling, induced by proteins tracking along the right‐handed DNA double helix, came into the limelight. Indeed, a number of observations now suggest that helix tracking‐induced DNA structural information might be exploited to participate in the regulation of a variety of DNA transactions in vivo. (shrink)

The lateral mobility of membrane lipids and proteins is presumed to play an important functional role in biomembranes. Photobleaching studies have shown that many proteins in the plasma membrane have diffusion coefficients at least an order of magnitude lower than those obtained when the same proteins are reconstituted in artificial bilayer membranes. Depending on the protein, it has been shown that either the cytoplasmic domain or the ectodomain is the key determinant of its lateral mobility. Single particle tracking microscopy, (...) which allows the motions of single or small groups of membrane molecules to be followed, promises not only to reveal new features of membrane dynamics, but also to help explain longstanding puzzles presented by the photobleaching studies, particularly the so‐called immobile fraction. The combination of the two complementary technologies should measurably enhance our understanding of membrane microstructure. (shrink)

In this powerful work of conceptual and analytical originality, the author argues for the primacy of the material arrangements of the laboratory in the dynamics of modern molecular biology. In a post-Kuhnian move away from the hegemony of theory, he develops a new epistemology of experimentation in which research is treated as a process for producing epistemic things. A central concern of the book is the basic question of how novelty is generated in the empirical sciences. In addressing this (...) question, the author brings French poststructuralist thinking—notably Jacques Derrida’s concepts of “différance” and “historiality”—to bear on the construction of epistemic things. Historiographical perspective shifts from the actors’ minds to their objects of manipulation. These epistemological and historical issues are illuminated in a detailed case study of a particular laboratory, that of the oncologist and biochemist Paul C. Zamecnik and his colleagues, located in a specific setting—the Collis P. Huntington Memorial Hospital of Harvard University at the Massachusetts General Hospital of Boston. The author traces how, between 1945 and 1965, this group developed an experimental system for synthesizing proteins in the test tube that put Zamecnik’s research team at the forefront of those who led biochemistry into the era of molecular biology. (shrink)

The complexity of the Hedgehog (Hh) signaling cascade has increased over the course of evolution; however, it does not suffice to accommodate the dynamic yet robust requirements of differential Hh signaling activity needed for embryonic development and adult homeostatic maintenance. One solution to solve this dilemma is to apply multiple forms of post‐translational modifications (PTMs) to the core Hh signaling components, modulating their abundance, localization, and signaling activity. This review summarizes various forms of protein modifications utilized to regulate Hh (...) signaling, with a special emphasis on crosstalk between different forms of PTMs and their feedback regulation by Hh signaling. (shrink)

TPPP/p25 is a recently discovered, unstructured protein involved in brain function. It is found predominantly in oligodendrocytes in normal brain but is enriched in neuronal and glial inclusions of Parkinson's disease and other synucleinopathies. Its physiological function seems to be the dynamic stabilization of microtubular ultrastructures, as well as the projections of mature oligodendrocytes and ciliary structures. We reappraise the earlier belief that TPPP/p25 is a brain‐specific protein. We have identified and cloned two shorter (N‐terminal‐free) homologs of TPPP/p25 (...) that behave differently from each other and from TPPP/p25. Two unique cell models have been established and used to study the effect of the unstructured protein on the energy metabolism and the formation of pathological aggregates. Our data suggest that the intracellular level of TPPP/p25 influences the cell differentiation, proliferation and the formation of protein aggregates, and consequently, the etiology of central nervous system diseases. (shrink)

The protein Po has long been proposed to be responsible for the compact nature of peripheral myelin through interactions of both its extracellular and cytoplasmic domains. Recent studies support such a role for Po's extracellular region while more precise mapping of its adhesive domains are ongoing. As Po is a member of the immunoglobulin gene superfamily and perhaps bears the closest similarity to the ancestral molecule of this whole family, these studies may also have more general implications for adhesive (...) interactions. In addition, although long believed to be purely an inert, structural molecule, Po has been reported to promote neurite outgrowth, which suggests a more dynamic role for this interesting molecule. (shrink)

In metazoans, the extracellular matrix (ECM) provides a dynamic, heterogeneous microenvironment that has important supportive and instructive roles. Although the primary site of action of ECM proteins is extracellular, evidence is emerging for non‐canonical intracellular roles. Examples include osteopontin, thrombospondins, IGF‐binding protein 3 and biglycan, and relate to roles in transcription, cell‐stress responses, autophagy and cancer. These findings pose conceptual problems on how proteins signalled for secretion can be routed to the cytosol or nucleus, or can function in environments (...) with diverse redox, pH and ionic conditions. We review evidence for intracellular locations and functions of ECM proteins, and current knowledge of the mechanisms by which they may enter intracellular compartments. We evaluate the experimental methods that are appropriate to obtain rigorous evidence for intracellular localisation and function. Better insight into this under‐researched topic is needed to decipher the complete spectrum of physiological and pathological roles of ECM proteins. -/- . (shrink)

The nuclear envelope has recently become the object of intense scrutiny because it is the site of nuclear transport and is possibly involved in the organization of the interphase genome, thereby affecting gene expression. The major structural support for the nuclear envelope is the nuclear lamina, composed of the nuclear lamin proteins. They lie on the surface of the inner nuclear membrane and are in direct contact with the chromatin at the edge of the nucleus. The structure of the nuclear (...) lamin proteins has recently been deduced from their cDNAs and shown to have remarkable homologies to the family of cytoplasmic intermediate filaments. However, the lamin proteins have been found to depolymerize in response to metaphase‐specific phosphorylation events, and reassemble around daughter chromosomes at the completion of cell division. Little is known of the mechanisms of these dynamics, nor of other post‐translational modifications evident in these proteins. In addition, we have as yet no concrete idea of the function of these highly conserved proteins in the cell. This review will summarize our present knowledge of nuclear lamin structure and the new experimental approaches designed to elucidate their function. (shrink)

Protein turnover (PT) has been formally defined only in equilibrium conditions, which is ill‐suited to quantify PT during dynamic processes that occur during embryogenesis or (extra) cellular signaling. In this Hypothesis, we propose a definition of PT in an out‐of‐equilibrium regime that allows the quantification of PT in virtually any biological context. We propose a simple mathematical and conceptual framework applicable to a broad range of available data, such as RNA sequencing coupled with pulsed‐SILAC datasets. We apply our framework (...) to a published dataset and show that stimulation of mouse dendritic cells with LPS leads to a proteome‐wide change in PT. This is the first quantification of PT out‐of‐equilibrium, paving the way for the analysis of biological systems in other contexts. (shrink)

While innovations in modern microscopy, spectroscopy, and nanoscopy techniques have made single molecule observation a standard in many laboratories, the actual design of meaningful fluorescence reporter systems now hinders major scientific breakthroughs. Even though the field of chemical biology is supercharging the fluorescence toolbox, surprisingly few strategies exist that make the transition from model systems to biologically relevant applications. At the same time, the number of microscopy techniques is growing dramatically. We explain our view on how the impact of modern (...) technologies is influenced not only by further hard‐ and software developments, but also by the availability and suitability of protein‐engineering tools. We identify how the largely independent research fields of chemical biology and fluorescence nanoscopy can influence each other to synergistically drive future technology that can visualize the localization, structure, and dynamics of molecular function without constraints. (shrink)

Post‐transcriptional regulation faces a distinctive challenge in gametes. Transcription is limited when the germ cells enter the division phase due to condensed chromatin, while gene expression during gamete maturation, fertilization, and early cleavage depends on existing mRNA post‐transcriptional coordination. The dynamics of the 3ʹ‐poly(A) tail play crucial roles in defining mRNA fate. The 3ʹ‐poly(A) tail is covered with poly(A)‐binding proteins (PABPs) that help to mediate mRNA metabolism and recent work has shed light on the number and function of germ (...) cell‐specific expressed PABPs. There are two structurally different PABP groups distinguished by their cytoplasmic and nuclear localization. Both lack catalytic activity but are coupled with various roles through their interaction with multifunctional partners during mRNA metabolism. Here, we present a synopsis of PABP function during gametogenesis and early embryogenesis and describe both conventional and current models of the functions and regulation of PABPs, with an emphasis on the physiological significance of how germ cell‐specific PABPs potentially affect human fertility. (shrink)

Recent advances in genomic and imaging techniques have revealed the complex manner of organizing billions of base pairs of DNA necessary for maintaining their functionality and ensuring the proper expression of genetic information. The SMC proteins and cohesin complex primarily contribute to forming higher‐order chromatin structures, such as chromosomal territories, compartments, topologically associating domains (TADs) and chromatin loops anchored by CCCTC‐binding factor (CTCF) protein or other genome organizers. Cohesin plays a fundamental role in chromatin organization, gene expression and regulation. (...) This review aims to describe the current understanding of the dynamic nature of the cohesin‐DNA complex and its dependence on cohesin for genome maintenance. We discuss the current 3C technique and numerous bioinformatics pipelines used to comprehend structural genomics and epigenetics focusing on the analysis of Cohesin‐centred interactions. We also incorporate our present comprehension of Loop Extrusion (LE) and insights from stochastic modelling. (shrink)

Molecular chaperones in cells constantly monitor and bind to exposed hydrophobicity in newly synthesized proteins and assist them in folding or targeting to cellular membranes for insertion. However, proteins can be misfolded or mistargeted, which often causes hydrophobic amino acids to be exposed to the aqueous cytosol. Again, chaperones recognize exposed hydrophobicity in these proteins to prevent nonspecific interactions and aggregation, which are harmful to cells. The chaperone‐bound misfolded proteins are then decorated with ubiquitin chains denoting them for proteasomal degradation. (...) It remains enigmatic how molecular chaperones can mediate both maturation of nascent proteins and ubiquitination of misfolded proteins solely based on their exposed hydrophobic signals. In this review, we propose a dynamic ubiquitination and deubiquitination model in which ubiquitination of newly synthesized proteins serves as a “fix me” signal for either refolding of soluble proteins or retargeting of membrane proteins with the help of chaperones and deubiquitinases. Such a model would provide additional time for aberrant nascent proteins to fold or route for membrane insertion, thus avoiding excessive protein degradation and saving cellular energy spent on protein synthesis. Also see the video abstract here: https://youtu.be/gkElfmqaKG4. (shrink)

Rho/Rac proteins constitute a subgroup of the Ras superfamily of GTP hydrolases. Although originally implicated in the control of cytoskeletal events, it is currently known that these GTPases coordinate diverse cellular functions, including cell polarity, vesicular trafficking, the cell cycle and transcriptomal dynamics. In this review, we will provide an overview on the recent advances in this field regarding the mechanism of regulation and signaling, and the roles in vivo of this important GTPase family. BioEssays 29:356–370, 2007. © 2007 (...) Wiley Periodicals, Inc. (shrink)

Secreted Frizzled‐related proteins (SFRPs) are modulators of the intermeshing pathways in which signals are transduced by Wnt ligands through Frizzled (Fz) membrane receptors. The Wnt networks influence biological processes ranging from developmental cell fate, cell polarity and adhesion to tumorigenesis and apoptosis. In the five or six years since their discovery, the SFRPs have emerged as dynamically expressed proteins able to bind both Wnts and Fz, with distinctive structural properties in which cysteine‐rich domains from Fz‐ and from netrin‐like proteins are (...) juxtaposed. The abundant expression of SFRP genes in the early embryo, altered expression patterns in disease states, and potential significance in the evolution of the vertebrate body plan, make these intriguing molecules relevant to investigations in diverse fields of biology and biomedical sciences. BioEssays 24:811–820, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Protein α-helices provide an ordered biological environment that is conducive to soliton-assisted energy transport. The nonlinear interaction between amide I excitons and phonon deformations induced in the hydrogen-bonded lattice of peptide groups leads to self-trapping of the amide I energy, thereby creating a localized quasiparticle (soliton) that persists at zero temperature. The presence of thermal noise, however, could destabilize the protein soliton and dissipate its energy within a finite lifetime. In this work, we have computationally solved the system (...) of stochastic differential equations that govern the quantum dynamics of protein solitons at physiological temperature, T=310 K, for either a single isolated α-helix spine of hydrogen bonded peptide groups or the full protein α-helix comprised of three parallel α-helix spines. The simulated stochastic dynamics revealed that although the thermal noise is detrimental for the single isolated α-helix spine, the cooperative action of three amide I exciton quanta in the full protein α-helix ensures soliton lifetime of over 30 ps, during which the amide I energy could be transported along the entire extent of an 18-nm-long α-helix. Thus, macromolecular protein complexes, which are built up of protein α-helices could harness soliton-assisted energy transport at physiological temperature. Because the hydrolysis of a single adenosine triphosphate molecule is able to initiate three amide I exciton quanta, it is feasible that multiquantal protein solitons subserve a variety of specialized physiological functions in living systems. (shrink)

Here I discuss findings that suggest a universal mechanism for proteins (and RNA) to recognize and interact with various binding partners by selectively binding to different conformations that pre‐exist in the free protein's conformational ensemble. The tandem RNA recognition motif domains of splicing factor U2AF65 fluctuate in solution between a predominately closed conformation in which the RNA binding site of one of the domains is blocked, and a lowly populated open conformation in which both RNA binding pockets are accessible. (...) RNA binding to U2AF65 may thus occur through the weakly populated open conformation, and the binding interaction stabilizes the open conformation. The conformational diversity observed in U2AF65 might also facilitate binding to diverse RNA sequences as found in the polypyrimidine tracts that help define 3′ splice sites. Similar binding pathways in other systems have important consequences in biological regulation, molecular evolution, and information storage. (shrink)

Schistosomes are parasitic blood flukes, responsible for significant human disease in tropical and developing nations. Here we review information on the organization of the cytoskeleton and associated motor proteins of schistosomes, with particular reference to the organization of the syncytial tegument, a unique cellular adaptation of these and other neodermatan flatworms. Extensive EST databases show that the molecular constituents of the cytoskeleton and associated molecular systems are likely to be similar to those of other eukaryotes, although there are potentially some (...) molecules unique to schistosomes and platyhelminths. The biology of some components, particular those contributing to host–parasite interactions as well as chemotherapy and immunotherapy are discussed. Unresolved questions in relation to the structure and function of the tegument relate to dynamic organization of the syncytial layer. BioEssays 26:752–765, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Biological order provided by α-helical secondary protein structures is an important resource exploitable by living organisms for increasing the efficiency of energy transport. In particular, self-trapping of amide I energy quanta by the induced phonon deformation of the hydrogen-bonded lattice of peptide groups is capable of generating either pinned or moving solitary waves following the Davydov quasiparticle/soliton model. The effect of applied in-phase Gaussian pulses of amide I energy, however, was found to be strongly dependent on the site of (...) application. Moving solitons were only launched when the amide I energy was applied at one of the α-helix ends, whereas pinned solitons were produced in the α-helix interior. In this paper, we describe a general mechanism that launches moving solitons in the interior of the α-helix through phase-modulated Gaussian pulses of amide I energy. We also compare the predicted soliton velocity based on effective soliton mass and the observed soliton velocity in computer simulations for different parameter values of the isotropy of the exciton-phonon interaction. The presented results demonstrate the capacity for explicit control of soliton velocity in protein α-helices, and further support the plausibility of gradual optimization of quantum dynamics for achieving specialized protein functions through natural selection. (shrink)

Spatiotemporal regulation of the biochemical information is often linked to supramolecular organizations proteins and nucleic acids, the driving forces of which have yet to be elucidated. Although the critical role of multivalency in phase transition has been recognized, the organization principles of higher-order structures need to be understood. Here, we present a fuzzy mathematical framework to handle the heterogeneity of interactions patterns and the resultant multiplicity of conformational states in protein assemblies. In this model, redundant binding motifs can establish (...) simultaneous and partial interactions with multiple targets. We demonstrate that these multivalent, weak contacts facilitate polymer formation, while recapitulating the observed valency-dependence. In addition, the impact of linker dynamics and motif binding affinity, as well as the interplay between the two effects was studied. Our results support that fuzziness is a critical factor in driving higher-order protein organizations, and this could be used as a general framework to simulate different kinds of supramolecular assemblies. (shrink)

We now know the structures of over 200 proteins to atomic resolution. Despite the impressive extent and quality of the results, crystal‐structure analysis has often been thought of as limited in scope, not only in its restriction to samples that can be crystallized, but in the more important respect that taking ‘snapshots’ of proteins does not directly address the complex spatio‐temporal organization of the processes in which proteins participate. It is suggested here that, as the field has matured, this second (...) limitation is gradually being overcome. As we gain increased access to structures of proteins in different conformational states – for example, in conformations produced by different states of ligation – and to families of homologous proteins, we can proceed from the statics of protein structure to the dynamics of conformational change, function, and evolution.A new scientific speciality has grown up around the solved structures: it has as its goal the elucidation of general principles of protein structure and function, to provide a theoretical framework for understanding the properties of proteins revealed by experiment. In this article we shall discuss some of the activity in this field. It will emerge clearly, I believe, that the increasing number and variety of solved structures is exerting a cumulative force. General principles are emerging from comparisons of related proteins and contrasts of dissimilar ones: the whole corpus of data is greater than the sum of the parts. (shrink)

Ubiquitination plays a central role in the regulation of stem cell self‐renewal, propagation, and differentiation. In this review, the functions of ubiquitin dynamics in a myriad of cellular processes, acting along side the pluripotency network, to regulate embryonic stem cell identity are highlighted. The implication of deubiquitinases (DUBs) and E3 Ubiquitin (Ub) ligases in cellular functions beyond protein degradation is reported, including key functions in the regulation of mRNA stability, protein translation, and intra‐cellular trafficking; and how it (...) affects cell metabolism, the micro‐environment, and chromatin organization is discussed. Finally, unsolved issues in the field are emphasized and will need to be tackled in order to fully understand the contribution of ubiquitin dynamics to stem cell self‐renewal and differentiation. (shrink)

The molecular biology of viruses can be effectively described by kinetic logic as several feedback loops are implicated in all viral cycles and as viral proteins generally display several functions. We applied this method to the study of the rhabdovirus cycle.Formally, the dynamics of the model are explored on the basis of a discrete caricature (kinetic logic), with special emphasis on the role of the constitutive feedback loops to determine the essential dynamical behaviour of the viral cycle. From a (...) biological point of view, our model accounts for several stable regimes or attractors: healthy cells, acute infection and different kinds of persistent infections, a multistationarity in good agreement with the existence of several positive feedback loops in our system. (shrink)

Site‐specific phosphorylation of intermediate filament (IF) proteins on serine and threonine residues leads to alteration of the filament structure, in vitro and in vivo. Protein kinases involved in cell signaling and those activated in mitosis dynamically control spatial and temporal organization of intracellular IF phosphorylation. Thus, IF phosphorylation appears to be one of the most predominant strategies in coordinating intracellular organization of the IF network.

The bacterial pathogen Listeria monocytogenes displays the remarkable ability to reorganize the actin cytoskeleton within host cells as a means for promoting cell‐to‐cell transfer of the pathogen, in a manner that evades humoral immunity. In a series of events commencing with the biosynthesis of the bacterial surface protein ActA, host cell actin and many actin‐associated protein self‐assemble to from rocket‐tail structures that continually grow at sites proximal to the bacterium and depolymerize distally. Widespread interest in the underlying molecular (...) mechanism of Listeria locomotion stems from the likelihood that the dynamic remodeling of the host cell actin cytoskeleton at the cell's leading edge involves mechanistically analogous interactions. Recent advances in our understanding of these fundamental cytoskeletal rearrangements have been achieved through a clearer recognition of the central role of oligo‐proline sequence repeats present in ActA, and these findings provide a basis for inferring the role of analogous host cell proteins in the force‐producing and position‐securing steps in pseudopod and lamellipod formation at the peripheral membrane. (shrink)

Complex functions of the central nervous system such as learning and memory are believed to result from the modulation of the synaptic transmission between neurons. The sequence of events leading to the fusion of synaptic vesicles at the presynaptic active zone and the detection of this signal at the postsynaptic density involve the activity of ion channels and neurotransmitter receptors. Their accumulation and dynamic exchange at synapses are dependent on their interaction with synaptic scaffolds. These are synaptic structures composed of (...) adaptor proteins that provide binding sites for receptors and channels as well as other synaptic proteins. While in its entirety the synaptic scaffold is a relatively stable structure, individual adaptor proteins exchange at a fast time scale. These properties of scaffolds help to ensure the stability of synaptic transmission while permitting the modulation of synaptic strength. Here, we review the dynamics of the synaptic scaffold and of adaptor proteins in relation to their roles in the organisation of the synapse as well as in the clustering and trafficking of receptor proteins. BioEssays 30:1062–1074, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

The recognition of extracellular molecules by cell surface receptors is the principal mechanism used by cells to sense their environment. Consequently, signals transduced as a result of these interactions make a major contribution to the regulation of cellular phenotype. Historically, particular emphasis has been placed on elucidating the intracellular consequences of growth factor and cytokine binding to cells. In addition to these interactions, however, cells are usually in intimate contact with a further source of complex structural and functional information, namely (...) immobilised extracellular matrix and/or cell surface adhesion proteins. A key question in recent years has been whether cells use the myriad of adhesion protein‐receptor interactions purely for structural and migratory function, or whether these interactions also make a more varied contribution to cell phenotype. Here we review dynamic aspects of the function of one major class of adhesion receptor, the integrins. In particular, we focus on the evidence for shape changes in integrin molecules, the mechanisms responsible for regulating ligand binding, and the signals transduced following integrin occupancy. (shrink)

The essential biological processes that sustain life are catalyzed by protein nano-engines, which maintain living systems in far-from-equilibrium ordered states. To investigate energetic processes in proteins, we have analyzed the system of generalized Davydov equations that govern the quantum dynamics of multiple amide I exciton quanta propagating along the hydrogen-bonded peptide groups in α-helices. Computational simulations have confirmed the generation of moving Davydov solitons by applied pulses of amide I energy for protein α-helices of varying length. The (...) stability and mobility of these solitons depended on the uniformity of dipole-dipole coupling between amide I oscillators, and the isotropy of the exciton-phonon interaction. Davydov solitons were also able to quantum tunnel through massive barriers, or to quantum interfere at collision sites. The results presented here support a nontrivial role of quantum effects in biological systems that lies beyond the mechanistic support of covalent bonds as binding agents of macromolecular structures. Quantum tunneling and interference of Davydov solitons provide catalytically active macromolecular protein complexes with a physical mechanism allowing highly efficient transport, delivery, and utilization of free energy, besides the evolutionary mandate of biological order that supports the existence of such genuine quantum phenomena, and may indeed demarcate the quantum boundaries of life. (shrink)

Microtubules form a highly dynamic filament network in all eukaryotic cells. Individual microtubules grow by tubulin dimer subunit addition and frequently switch between phases of growth and shortening. These unique dynamics are powered by GTP hydrolysis and drive microtubule network remodeling, which is central to eukaryotic cell biology and morphogenesis. Yet, our knowledge of the molecular events at growing microtubule ends remains incomplete. Here, recent ultrastructural, biochemical and cell biological data are integrated to develop a realistic model of growing (...) microtubule ends comprised of structurally distinct but biochemically overlapping zones. Proteins that recognize microtubule lattice conformations associated with specific tubulin guanosine nucleotide states may independently control major structural transitions at growing microtubule ends. A model is proposed in which tubulin dimer addition and subsequent closure of the MT wall are optimized in cells to achieve rapid physiological microtubule growth. (shrink)