The coupling of protein synthesis and folding is a crucial yet poorly understood aspect of cellular protein folding. Over the past few years, it has become possible to experimentally follow and define protein folding on the ribosome, revealing principles that shape co‐translational folding and distinguish it from refolding in solution. Here, we highlight some of these recent findings from biochemical and biophysical studies and their potential significance for cellular protein biogenesis. In (...) particular, we focus on nascent chain interactions with the ribosome, interactions within the nascent protein, modulation of translation elongation rates, and the role of mechanical force that accompanies nascent protein folding. The ability to obtain mechanistic insight in molecular detail has set the stage for exploring the intricate process of nascent protein folding. We believe that the aspects discussed here will be generally important for understanding how protein synthesis and folding are coupled and regulated. (shrink)

Fold‐switching proteins, which remodel their secondary and tertiary structures in response to cellular stimuli, suggest a new view of protein fold space. For decades, experimental evidence has indicated that protein fold space is discrete: dissimilar folds are encoded by dissimilar amino acid sequences. Challenging this assumption, fold‐switching proteins interconnect discrete groups of dissimilar protein folds, making protein fold space fluid. Three recent observations support the concept of fluid fold space: (1) some amino acid sequences interconvert between (...) folds with distinct secondary structures, (2) some naturally occurring sequences have switched folds by stepwise mutation, and (3) fold switching is evolutionarily selected and likely confers advantage. These observations indicate that minor amino acid sequence modifications can transform protein structure and function. Consequently, proteomic structural and functional diversity may be expanded by alternative splicing, small nucleotide polymorphisms, post‐translational modifications, and modified translation rates. (shrink)

The process of protein folding in the cell is now known to depend on the action of other proteins. These proteins include molecular chaperones, Which interact non‐covalently with proteins as they fold and improve the final yields of active protein in the cell. The precise mechanism by which molecular chaperones act is obscure. Experiments reported recently(1) show that for one molecular chaperone (Cpn60, typified by the E. coli protein GroEL), the folding reaction is driven by (...) cycles of binding and release of the co‐chaperone Cpn10 (known as GroES in E. coli). These alternate with binding and release of the unfolded protein substrate. These cycles come about because of the opposite effects of Cpn10 and unfolded protein on the Cpn60 complex: the former stabilises the ADP‐bound state of Cpn60, whereas the latter stimulates ADP‐ATP exchange. This model proposes that the substrate protein goes through multiple cycles of binding and release, and is released into the cavity of the Cpn60 complex where it can undergo folding without interacting with other nearby folding intermediates. This is consistent with the ability of Cpn60 proteins to enhance folding by blocking pathways to aggregation. (shrink)

Complexes of two or more proteins form many, if not most, of the intracellular “machines” that execute physical and chemical work, and transmit information. Complexes can form from stochastic post‐translational interactions of fully formed proteins, but recent attention has shifted to co‐translational interactions in which the most common mechanism involves binding of a mature constituent to an incomplete polypeptide emerging from a translating ribosome. Studies in yeast have revealed co‐translational interactions during formation of multiple major complexes, and (...) together with recent mammalian cell studies, suggest widespread utilization of the mechanism. These translation‐dependent interactions can involve a single or multiple mRNA templates, can be uni‐ or bi‐directional, and can use multi‐protein sub‐complexes as a binding component. Here, we discuss benefits of co‐translational complex assembly including accuracy and efficiency, overcoming hidden interfaces, localized and hierarchical assembly, and reduction of orphan protein degradation, toxicity, and dominant‐negative pathogenesis, all serving to improve cell fitness. (shrink)

This text reconstructs the Kohlberg/Gilligan controversy between a male ethics of justice and a female ethics of care. Using Karl-Otto Apel's transcendental pragmatics, the author argues for a mediation between both models in terms of a reciprocal co-responsibility. Against this backdrop, she defends the circular procedure of an exclusively argumentative-reflexive justification of a normative ethics. From this it follows for feminist ethics that it cannot do without either of the two types of ethics. The goal is to assure the evaluative (...) variety of different types of an ethics of the good without endangering the normative boundaries of a deontological discourse ethics. (shrink)

Construction of the eukaryotic ribosome is a complex process in which a nascent ribosomal RNA (rRNA) emerging from RNA Polymerase I hierarchically folds into a native three‐dimensional structure. Modular assembly of individual RNA domains through interactions with ribosomal proteins and a myriad of assembly factors permit efficient disentanglement of the error‐prone RNA folding process. Following these dynamic events, long‐range tertiary interactions are orchestrated to compact rRNA. A combination of genetic, biochemical, and structural studies is now providing clues into how (...) a nascent rRNA is transformed into a functional ribosome with high precision. With this essay, we aim to draw attention to the poorly understood process of establishing correct RNA tertiary contacts during ribosome formation. (shrink)

This review portraits FK506 binding protein (FKBP) 51 as “reactivity protein” and collates recent publications to develop the concept of FKBP51 as contributor to different levels of adaptation. Adaptation is a fundamental process that enables unicellular and multicellular organisms to adjust their molecular circuits and structural conditions in reaction to environmental changes threatening their homeostasis. FKBP51 is known as chaperone and co‐chaperone of heat shock protein (HSP) 90, thus involved in processes ensuring correct protein folding (...) in response to proteotoxic stress. In mammals, FKBP51 both shapes the stress response and is calibrated by the stress levels through an ultrashort molecular feedback loop. More recently, it has been linked to several intracellular pathways related to the reactivity to drug exposure and stress. Through its role in autophagy and DNA methylation in particular it influences adaptive pathways, possibly also in a transgenerational fashion.Also see the video abstract here. (shrink)

In concert with the selective pressures affecting protein folding and function in the extreme environments in which they can exist, proteins in Archaea have evolved to present permanent molecular adaptations at the amino acid sequence level. Such adaptations may not, however, suffice when Archaea encounter transient changes in their surroundings. Post‐translational modifications offer a rapid and reversible layer of adaptation for proteins to cope with such situations. Here, it is proposed that Archaea further augment their ability to (...) survive changing growth conditions by modifying the extent, position, and, where relevant, the composition of different post‐translational modifications, as a function of the environment. Support for this hypothesis comes from recent reports describing how patterns of protein glycosylation, methylation, and other post‐translational modifications of archaeal proteins are altered in response to environmental change. Indeed, adjusting post‐translational modifications as a means to cope with environmental variability may also hold true beyond the Archaea. (shrink)

In a recent issue of Nature Communications Ukleja and co‐workers reported a cryo‐EM 3D reconstruction of the Ccr4‐Not complex from Schizosaccharomyces pombe with an immunolocalization of the different subunits. The newly gained architectural knowledge provides cues to apprehend the functional diversity of this major eukaryotic regulator. Indeed, in the cytoplasm alone, Ccr4‐Not regulates translational repression, decapping and deadenylation, and the Not module additionally plays a positive role in translation. The spatial distribution of the subunits within the structure is compatible (...) with a model proposing that the Ccr4‐Not complex interacts with the 5′ and 3′ ends of target mRNAs, allowing different functional modules of the complex to act at different stages of the translation process, possibly within a circular constellation of the mRNA. This work opens new avenues, and reveals important gaps in our understanding regarding structure and mode of function of the Ccr4‐Not complex that need to be addressed in the future. (shrink)

The origins and evolution of the Archaea, Bacteria, and Eukarya remain controversial. Phylogenomic‐wide studies of molecular features that are evolutionarily conserved, such as protein structural domains, suggest Archaea is the first domain of life to diversify from a stem line of descent. This line embodies the last universal common ancestor of cellular life. Here, we propose that ancestors of Euryarchaeota co‐evolved with those of Bacteria prior to the diversification of Eukarya. This co‐evolutionary scenario is supported by comparative genomic and (...) phylogenomic analyses of the distributions of fold families of domains in the proteomes of free‐living organisms, which show horizontal gene recruitments and informational process homologies. It also benefits from the molecular study of cell physiologies responsible for membrane phospholipids, methanogenesis, methane oxidation, cell division, gas vesicles, and the cell wall. Our theory however challenges popular cell fusion and two‐domain of life scenarios derived from sequence analysis, demanding phylogenetic reconciliation. (shrink)

Molecular chaperones facilitate the correct folding of other proteins under physiological and stress conditions. Recently it has become evident that various co‐chaperone proteins regulate the cellular functions of these chaperones, particularly Hsp70 and Hsp90. Hop is one of the most extensively studied co‐chaperones that is able to directly associate with both Hsp70 and Hsp90. The current dogma proposes that Hop functions primarily as an adaptor that directs Hsp90 to Hsp70‐client protein complexes in the cytoplasm. However, recent evidence suggests (...) that Hop can also modulate the chaperone activities of these Hsps, and that it is not dedicated to Hsp70 and Hsp90. While the co‐chaperone function of Hop within the cytoplasm has been extensively studied, its association with nuclear complexes and prion proteins remains to be elucidated. This article will review the structural features of Hop, and the evidence that its biological function is considerably broader than previously envisaged. BioEssays 26:1058–1068, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

As targeted proteins that move within the cell, the steroid receptors have become very useful probes for understanding the linked phenomena of protein folding and transport. From the study of steroid receptor‐associated proteins it has become clear over the past two years that these receptors are bound to a multiprotein complex containing at least two heat shock proteins, hsp90 and hsp56. Attachment of receptors to this complex in a cell‐free system appears to require the protein unfolding/folding (...) activity of a third heat shock protein, hsp70. Like the oncogenic tyrosine kinase pp60src, steroid receptors bind to this complex of chaperone proteins at the time of their translation. Binding of the receptor to the hsp90 component of the system occurs through the hormone binding domain and is under strict hormonal control. The hormone binding domain of the receptor acts as a transferable regulatory unit that confers both tight hormonal control and hsp90 binding onto chimaeric proteins. The model of folding and transport being developed for steroid receptors leads to some general suggestions regarding the folding and transport of targeted proteins in the cell. (shrink)

The unfertilized sea urchin egg is a metabolically quiescent cell. Fertilization results in the activation of a variety of metabolic and biosynthetic pathways, including a 20‐ to 40‐fold increase in the rate of protein synthesis by 2 h after fertilization. This increase is regulated at a purely translational level without the need for new transcription. The greatest part of this increase is due to the translation of stored maternal mRNAs which were not translated in the egg. There is (...) also a 2‐to 3‐fold increase in the peptide elongation rate. The molecular and physiological mechanisms responsible for this activation process are beginning to be understood, and turn out to be much more complex than was anticipated. (shrink)

In this paper we propose a theoretical model of protein folding and protein evolution in which a polypeptide (sequence/structure) is assumed to behave as a Maxwell Demon or Information Gathering and Using System (IGUS) that performs measurements aiming at the construction of the native structure. Our model proposes that a physical meaning to Shannon information (H) and Chaitin's algorithmic information (K) parameters can be both defined and referred from the IGUS standpoint. Our hypothesis accounts for the interdependence (...) of protein folding and protein evolution through mutual influencing relationships mediated by the IGUS. In brief, IGUS activity in protein folding determines long term tendencies that emerge at the evolutionary time-scale.Thus, protein evolution is a consequence of measurements executed by proteins at the cellular level, where the IGUS imposes a tendency to attain a highly unique stable native form that promotes the updating of the information content. The folding kinetics observed is, thus, the outcome of an evolutionary process where the polypeptide-IGUS drives the evolution of its linear sequence. Finally, we describe protein evolution as an entropic process that tends to increase the content of mutual algorithmic information between the sequence and the structure. This model enables one: 1. To comprehend that full determination of the three-dimensional structure by the linear sequence is a tendency where satisfaction is only possible at thermodynamic equilibrium .2. To account for the observed randomness of the amino acid sequences. 3. To predict an alternation of periods of selection and neutral diffusion during protein evolutionary time. (shrink)

To explore whether the generation of new protein folds could be linked to metallic cofactor recruitment, we identified the oldest examples of folds for manganese, iron, zinc, and copper proteins by analyzing their fold‐domain mapping patterns. We discovered that the generation of these folds was tightly coupled to corresponding metals. We found that the emerging order for these folds, i.e., manganese and iron protein folds appeared earlier than zinc and copper counterparts, coincides with the putative bioavailability of the (...) corresponding metals in the ancient anoxic ocean. Therefore, we conclude that metallic cofactors, like organic cofactors, play an evolutionary role in the formation of new protein folds. This link could be explained by the emergence of protein structures with novel folds that could fulfill the new protein functions introduced by the metallic cofactors. These findings not only have important implications for understanding the evolutionary mechanisms of protein architectures, but also provide a further interpretation for the evolutionary story of superoxide dismutases. (shrink)

The protein folding problem is one of the foundational problems of biochemistry and it is still considered unsolved. It basically consists of two main questions: what are the factors determining the stability of the protein’s native structure and how does the protein acquire it starting from an unfolded state. Since its first formulation, two main explanatory approaches have dominated the field of protein folding research: a thermodynamic approach focused on energetic features and a kinetic (...) approach focused on the temporal development of protein chains and structural considerations. Although these two approaches are tightly intertwined in biochemical practice and largely agree on which are the parts and activities in which the phenomenon under study should be decomposed to, there nevertheless exist important contrasts that have had repercussions on the development of the field and still engender vigorous debate. We shall analyse the historical development of the field and crucial aspects of current scientific debates. On this basis, we argue that the main sources of disagreement centre on the causal interpretation of thermodynamic and kinetic explanations, on the explanatory relevance assigned to different features of the phenomena under study and on the status of the ontological assumptions concerning the entities under study. (shrink)

The best‐characterized model pathway of protein folding, that of disulphide bond formation in the small protein BPTI, has been questioned recently. A reinvestigation of that pathway, using alternative methods, concluded that the intermediates with non‐native disulphide bonds accumulated to lower levels than previously had been observed(17). On this basis, a revised pathway was proposed that simply omitted those intermediates. Even if totally correct, however, the new observations are not inconsistent with the important characteristics of the original pathway (...) and even confirmed many of them. Certain crucial observations that were the experimental basis for the original pathway were ignored, and these observations invalidate the revised pathway. (shrink)

The discovery of “molecular chaperones” has dramatically changed our concept of cellular protein folding. Rather than folding spontaneously, most newly synthesized polypeptide chains seem to acquire their native conformation in a reaction mediated by these versatile helper proteins. Understanding the structure and function of molecular chaperones is likely to yield useful applications for medicine and biotechnology in the future.

A crucially important part of the biosphere – the virosphere – is too often overlooked. Inclusion of the virosphere into the global picture of protein structure space reveals that 63 protein domain superfamilies in viruses do not have any structural and evolutionary relatives in modern cellular organisms. More than half of these have functions which are not virus‐specific and thus might be a source of new folds and functions for cellular life. The number of viruses on the planet (...) exceeds that of cells by an order of magnitude and viruses evolve up to six orders of magnitude faster. As a result, cellular species are subject to a constitutive ‘flow‐through’ of new viral genetic material. Due to this and the relaxed evolutionary constraints in viruses, the transfer of domains between host‐to‐virus could be a mechanism for accelerated protein evolution. The virosphere could be an engine for the genesis of protein structures, and may even have been so before the last universal common ancestor of cellular life. (shrink)

In this paper I attempt to study the notion of “folding of a semiotic continuum” in a direction of a possible application to the biological processes. More specifically, the process of obtaining protein structures is compared in this paper to the folding of a semiotic continuum. Consequently, peptide chain is presented as a continuous line potential to be formed in order to create functional units. The functional units are protein structures having certain function in the cell (...) or organism. Moreover, protein folding is analyzed in terms of tension between syntax and semantics. (shrink)

Prediction is more than testing established theory by examining whether the prediction matches the data. To show this, I examine the practices of a community of scientists, known as threaders, who are attempting to predict the final, folded structure of a protein from its primary structure, i.e., its amino acid sequence. These scientists employ a careful and deliberate methodology of prediction. A key feature of the methodology is calibration. They calibrate in order to construct better models. The construction leads (...) to knowledge of how to construct or build an object. Thus, prediction serves a cognitive goal of model construction and not just model or theory testing. The kind of knowledge that results is relevantly different than theoretical knowledge. (shrink)

We suggest a new view of secretory and membrane protein folding that emphasizes the role of pathways of biogenesis in generating functional and conformational heterogeneity. In this view, heterogeneity results from action of accessory factors either directly binding specific sequences of the nascent chain, or indirectly, changing the environment in which a particular domain is synthesized. Entrained by signaling pathways, these variables create a combinatorial set of necessary‐but‐not‐sufficient conditions that enhance synthesis and folding of particular alternate, functional, (...) conformational forms. We therefore propose that protein conformation is productively regulated by the cell during translocation across the endoplasmic reticulum (ER), a concept that may account for currently poorly understood aspects of physiological function, natural selection, and disease pathogenesis. BioEssays 24:741–748, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Mutagenesis makes it possible to examine the effect of amino acid replacements on the folding and stability of proteins. The evaluation of kinetic and equilibrium folding data using reaction coordinate diagrams allows one to determine the roles that single amino acids play in the folding mechanism.

We develop a general method for applying functional models to natural systems and cite recent progress in protein modeling that demonstrates the power of this approach. Functional modeling constrains the range of acceptable structural models of a system, reduces the difficulty of finding them, and improves their fidelity. However, functional models are distinctly different from the structural models that are more commonly applied in science. In particular, structural and functional models ask different questions and provide different kinds of answers. (...) As we clarify these differences and articulate how to use these models jointly, we extend our ability to do science and gain insight into the proper use of the terms organization , order , and emergence when describing systems in nature. (shrink)

The centriole is a widely conserved organelle required for the assembly of centrosomes, cilia, and flagella. Its striking feature – the nine‐fold symmetrical structure, was discovered over 70 years ago by transmission electron microscopy, and since elaborated mostly by cryo‐electron microscopy and super‐resolution microscopy. Here, we review the discoveries that led to the current understanding of how the nine‐fold symmetrical structure is built. We focus on the recent findings of the centriole structure in high resolution, its assembly pathways, and its (...) nine‐fold distributed components. We propose a model that the assembly of the nine‐fold symmetrical centriole depends on the concerted efforts of its core proteins. Also see the video abstract here:https://youtu.be/m4h_3II_WJo. (shrink)

The reovirus cell attachment protein σ1 is a lollipopshaped structure with the fibrous tail anchored to the virion. Since it interacts with the cell receptor, σ1 is a major determinant of reovirus infectivity and tissue tropism. Studies on its structure‐function relationships have been facilitated by the fact that protein σ1 produced in any expression system is capable of binding to cell receptors. The use of site‐specific and deletion mutants has led to the identification and characterization of its virion (...) anchorage and receptor binding domains. Studies on the oligomeric status of σ1 have revealed that σ1 is a homotrimer and that two independent trimerization events at different loci (the N‐ and C‐terminal halves, respectively) of the protein, are involved in its generation. This also accounts for a clearly demonstrable dominant negative effect by a mutant subunit in a wild‐type/mutant σ1 heterotrimer. Current efforts are focused on the involvement of chaperones in the generation of σ1 and on events that take place upon σ1 binding to the cell receptor. Protein σ1 has therefore become an excellent model system for the study of both virus attachment and protein oligomerization and folding mechanisms. (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)

The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co-transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the (...) biogenesis of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates. These small RNAs can then target the genomic regions from which they initially originate and increase the local mutation rate of the targeted loci. This mechanism is based on molecular pathways involved in anti-parasite genome defence systems, and implies that gene expression-related biophysical constraints represent a driving force of genome evolution. Are randomly generated mutations the only source of genetic variation during evolution? This paper describes the molecular mechanisms by which co-transcriptional and co-translational biophysical constraints trigger genetic variations in targeted-genomic sequences in an RNA-depending manner. This directed-mutational process that drives genome evolution is related to antiparasite genome defence systems. (shrink)

The expression of certain eukaryotic genes is – at least in part – controlled at the level of mRNA translation. The step of translational initiation represents the primary target for regulation. The regulation of the intracellular iron storage protein ferritin in response to iron levels provides a good example of translational control by a reversible RNA/protein interaction in the 5' untranslated region of an mRNA. We consider mechanisms by which mRNA/protein interactions may impede translation initiation (...) and discuss recent data suggesting that the ferritin example may represent the ‘tip of the iceberg’ of a more general theme for translational control. (shrink)

The pathway for initiation of protein synthesis in eukaryotic cells has been defined and refined over the last 25 years using purified components and in vitro reconstituted systems. More recently, powerful genetic analysis in yeast has proved useful in unraveling aspects of translation inherently more difficult to address by strictly biochemical approaches. One area in particular is the functional analysis of multi‐subunit protein factors, termed eukaryotic initiation factors (eIFs), that play an essential role in translation initiation. eIF‐3, the (...) most structurally complex of the eIFs, has until recently eluded this approach. The identification of the yeast GCD10 gene as the structural gene for the ζ subunit of yeast eIF‐3(1) and the analysis of mutant phenotypes has opened the door to the genetic dissection of the eIF‐3 protein complex. (shrink)

Protein post‐translational modifications (PTMs) play a crucial role in all cellular functions by regulating protein activity, interactions and half‐life. Despite the enormous diversity of modifications, various PTM systems show parallels in their chemical and catalytic underpinnings. Here, focussing on modifications that involve the addition of new elements to amino‐acid sidechains, I describe historical milestones and fundamental concepts that support the current understanding of PTMs. The historical survey covers selected key research programmes, including the study of protein (...) phosphorylation as a regulatory switch, protein ubiquitylation as a degradation signal and histone modifications as a functional code. The contribution of crucial techniques for studying PTMs is also discussed. The central part of the essay explores shared chemical principles and catalytic strategies observed across diverse PTM systems, together with mechanisms of substrate selection, the reversibility of PTMs by erasers and the recognition of PTMs by reader domains. Similarities in the basic chemical mechanism are highlighted and their implications are discussed. The final part is dedicated to the evolutionary trajectories of PTM systems, beginning with their possible emergence in the context of rivalry in the prokaryotic world. Together, the essay provides a unified perspective on the diverse world of major protein modifications. (shrink)

The ribosomal polypeptide tunnel exit is the site where a variety of factors interact with newly synthesized proteins to guide them through the early steps of their biogenesis. In mitochondrial ribosomes, this site has been considerably modified in the course of evolution. In contrast to all other translation systems, mitochondrial ribosomes are responsible for the synthesis of only a few hydrophobic membrane proteins that are essential subunits of the mitochondrial respiratory chain. Membrane insertion of these proteins occurs co‐translationally and is (...) connected to a sophisticated assembly process that not only includes the assembly of the different subunits but also the acquisition of redox co‐factors. Here, we describe how mitochondrial translation is organized in the context of respiratory chain assembly and speculate how alteration of the ribosomal tunnel exit might allow the establishment of a subset of specialized ribosomes that individually organize the early steps in the biogenesis of distinct mitochondrially‐encoded proteins. (shrink)

The fate of cellular RNAs is largely dependent on their structural conformation, which determines the assembly of ribonucleoprotein (RNP) complexes. Consequently, RNA‐binding proteins (RBPs) play a pivotal role in the lifespan of RNAs. The advent of highly sensitive in cellulo approaches for studying RNPs reveals the presence of unprecedented RNA‐binding domains (RBDs). Likewise, the diversity of the RNA targets associated with a given RBP increases the code of RNA–protein interactions. Increasing evidence highlights the biological relevance of RNA conformation for (...) recognition by specific RBPs and how this mutual interaction affects translation control. In particular, noncanonical RBDs present in proteins such as Gemin5, Roquin‐1, Staufen, and eIF3 eventually determine translation of selective targets. Collectively, recent studies on RBPs interacting with RNA in a structure‐dependent manner unveil new pathways for gene expression regulation, reinforcing the pivotal role of RNP complexes in genome decoding. (shrink)

tRNAs undergo multiple conformational changes during the translation cycle that are required for tRNA translocation and proper communication between the ribosome and translation factors. Recent structural data on how destabilized tRNAs utilize the CCA‐adding enzyme to proofread themselves put a spotlight on tRNA flexibility beyond the translation cycle. In analogy to tRNA surveillance, this review finds that other processes also exploit versatile tRNA folding to achieve, amongst others, specific aminoacylation, translational regulation by riboswitches or a block of bacterial (...) translation. tRNA flexibility is thereby not restricted to the hinges utilized during translation. In contrast, the flexibility of tRNA is distributed all over its L‐shape and is actively exploited by the tRNA‐interacting partners to discriminate one tRNA from another. Since the majority of tRNA modifications also modulate tRNA flexibility it seems that cells devote enormous resources to tightly sense and regulate tRNA structure. This is likely required for error‐free protein synthesis. (shrink)

The final assembly of the protein synthesis machinery occurs during translation initiation. This delicate process involves both ends of eukaryotic messenger RNAs as well as multiple sequential protein–RNA and protein–protein interactions. As is expected from its critical position in the gene expression pathway between the transcriptome and the proteome, translation initiation is a selective and highly regulated process. This synopsis summarises the current status of the field and identifies intriguing open questions. BioEssays 25:1201–1211, 2003 © 2003 (...) Wiley Periodicals, Inc. (shrink)

How the formidable diversity of forms emerges from developmental and evolutionary processes is one of the most fascinating questions in biology. The homeodomain‐containing Hox proteins were recognized early on as major actors in diversifying animal body plans. The molecular mechanisms underlying how this transcription factor family controls a large array of context‐ and cell‐specific biological functions is, however, still poorly understood. Clues to functional diversity have emerged from studies exploring how Hox protein activity is controlled through interactions with PBC (...) class proteins, also evolutionary conserved HD‐containing proteins. Recent structural data and molecular dynamic simulations add further mechanistic insights into Hox protein mode of action, suggesting that flexible folding of protein motifs allows for plastic protein interaction. As we discuss in this review, these findings define a novel type of Hox‐PBC interaction, weak and dynamic instead of strong and static, hence providing novel clues to understanding Hox transcriptional specificity and diversity. (shrink)