The genetic code has been regarded as arbitrary in the sense that the codon-amino acid assignments could be different than they actually are. This general idea has been spelled out differently by previous, often rather implicit accounts of arbitrariness. They have drawn on the frozen accident theory, on evolutionary contingency, on alternative causal pathways, and on the absence of direct stereochemical interactions between codons and amino acids. It has also been suggested that the arbitrariness of the genetic code justifies attributing (...) semantic information to macromolecules, notably to DNA. I argue that these accounts of arbitrariness are unsatisfactory. I propose that the code is arbitrary in the sense of Jacques Monod's concept of chemical arbitrariness: the genetic code is arbitrary in that any codon requires certain chemical and structural properties to specify a particular amino acid, but these properties are not required in virtue of a principle of chemistry. This notion of arbitrariness is compatible with several recent hypotheses about code evolution. I maintain that the code's chemical arbitrariness is neither sufficient nor necessary for attributing semantic information to nucleic acids. (shrink)

There is an urgent need for novel protection strategies to sustainably secure crop production under changing climates. Studying microbial effectors, defined as microbe‐derived proteins that alter signalling inside plant cells, has advanced our understanding of plant immunity and microbial plant colonisation strategies. Our understanding of effectors in the establishment and beneficial outcome of plant symbioses is less well known. Combining functional and comparative interaction assays uncovered specific symbiont effector targets in highly interconnected plant signalling networks and revealed the (...) potential of effectors in beneficially modulating plant traits. The diverse functionality of symbiont effectors differs from the paradigmatic immuno‐suppressive function of pathogen effectors. These effectors provide solutions for improving crop resilience against climate stress by their evolution‐driven specification in host protein targeting and modulation. Symbiont effectors represent stringent tools not only to identify genetic targets for crop breeding, but to serve as applicable agents in crop management strategies under changing environments. (shrink)

Motor inhibitory control, the ability to suppress unwanted actions, has been previously shown to rely on domain-general IC processes that are involved in a wide range of IC tasks. Nevertheless, the existence of effector-specific regions and activation patterns that would differentiate manual vs. oculomotor response inhibition remains unknown. In this study, we investigated the brain dynamics supporting these two response effectors with the same IC task paradigm. We examined the behavioral performance and electrophysiological activity in a group of healthy (...) young people with a Go/NoGo task using the index finger for the manual modality and the eyes for the oculomotor modality. By computing topographic analysis of variance, we found significant differences between topographies of scalp recorded potentials of the two response effectors between 250 and 325 ms post-stimulus onset. The source estimations localized this effect within the left precuneus, a part of the superior parietal lobule, showing stronger activity in the oculomotor modality than in the manual modality. Behaviorally, we found a significant positive correlation in response time between the two modalities. Our collective results revealed that while domain-general IC processes would be engaged across different response effectors in the same IC task, effector-specific activation patterns exist. In this case, the stronger activation of the left precuneus likely accounts for the increased demand for visual attentional processes in the oculomotor Go/NoGo task. (shrink)

Several studies have illuminated how processing manual action verbs (MaVs) affects the programming or execution of concurrent hand movements. Here, to circumvent key confounds in extant designs, we conducted the first assessment of motor–language integration during handwriting—a task in which linguistic and motoric processes are co‐substantiated. Participants copied MaVs, non‐manual action verbs, and non‐action verbs as we collected measures of motor programming and motor execution. Programming latencies were similar across conditions, but execution was faster for MaVs than for the other (...) categories, regardless of whether word meanings were accessed implicitly or explicitly. In line with the Hand‐Action‐Network Dynamic Language Embodiment (HANDLE) model, such findings suggest that effector‐congruent verbs can prime manual movements even during highly automatized tasks in which motoric and verbal processes are naturally intertwined. Our paradigm opens new avenues for fine‐grained explorations of embodied language processes. (shrink)

Phosphoinositides modulate a plethora of functions including signal transduction and membrane trafficking. PtdInsPs are thought to consist of seven interconvertible species that localize to a specific organelle, to which they recruit a set of cognate effector proteins. Here, in reviewing the literature, we argue that this model needs revision. First, PtdInsPs can carry a variety of acyl chains, greatly boosting their molecular diversity. Second, PtdInsPs are more promiscuous in their localization than is usually acknowledged. Third, PtdInsP interconversion is likely achieved (...) through kinase-phosphatase enzyme complexes that coordinate their activities and channel substrates without affecting bulk substrate population. Additionally, we contend that despite hundreds of PtdInsP effectors, our attention is biased toward few proteins. Lastly, we recognize that PtdInsPs can act to nucleate coincidence detection at the effector level, as in PDK1 and Akt. Overall, better integrated models of PtdInsP regulation and function are not only possible but needed. Phosphoinositides are lipids that control many cellular functions. However, the field of PtdInsP signaling is dominated by several dogmatic notions. Here, we offer an updated glimpse on the current state of the field regarding molecular diversity, localization, organization of modifying enzymes, effector types, and effector organization. (shrink)

Recent theory suggests that action prediction relies of a motor emulation mechanism that works by mapping observed actions onto the observer action system so that predictions can be generated using that same predictive mechanisms that underlie action control. This suggests that action prediction may be more accurate when there is a more direct mapping between the stimulus and the observer. We tested this hypothesis by comparing prediction accuracy for two stimulus types. A mannequin stimulus which contained information about the (...) class='Hi'>effectors used to produce the action and a point stimulus, which contained identical dynamic information but no effector information. Prediction was more accurate for the mannequin stimulus. However, this effect was dependent on the observer having previous experience performing the observed action. This suggests that experienced and na¨ıve observers might generate predictions in qualitatively difference ways, which may relate to the presence of an internal representation of the action laid down through action performance. (shrink)

The immune system has evolved to detect and remove foreign or non‐self molecules from the body. To perform this task, the system has coupled together specific recognition with non‐specific effector mechanisms in at least two distinct fashions, as outlined in this review.

RAS GTPases play essential roles in normal development and are direct drivers of human cancers. Three decades of study have failed to wholly characterize pathways stimulated by activated RAS, driven by engagement with ‘effector’ proteins that have RAS binding domains (RBDs). Bone fide effectors must bind directly to RAS GTPases in a nucleotide‐dependent manner, and this interaction must impart a clear change in effector activity. Despite this, for most proteins currently deemed effectors there is little mechanistic understanding of (...) how binding to the GTPase alters protein function. There has also been limited effort to comprehensively resolve the specificity of effector binding to the full array of RAS superfamily GTPase proteins. This review will summarize what is known about RAS‐driven activation for an array of potential effector proteins, focusing on structural and mechanistic effects and highlighting how little is still known regarding this key paradigm of cellular signal transduction. (shrink)

The fructose 6-phosphate (Fru-6P) saturation curve for phosphofructokinase (PFK) from E. coli is sigmoidal in the presence of saturating MgATP levels, while the corresponding curve for B. stearothermophilus PFK is essentially hyperbolic. Sigmoidality can be due to apparent cooperativity arising from the kinetic mechanism of an enzyme. We have determined the kinetic mechanism of B. stearothermophilus PFK (BsPFK). BsPFK was found to obey a non rapid-equilibrium random mechanism similar to the one E. coli PFK (EcPFK) follows. Substrate inhibition by MgATP (...) was observed. We propose that substrates bind to BsPFK through two alternative pathways, one of which is slower. The substrate inhibition arises in part from reaction flux through the slower pathway. Although EcPFK and BsPFK obey similar kinetic mechanisms, they are inhibited differently by MgATP: EcPFK is profoundly inhibited, BsPFK only weakly. The structural basis for this difference could be closure of the active site via a conformational transition that occurs in EcPFK, but not BsPFK. To investigate the importance of this transition for MgATP inhibition of EcPFK, we have constructed a chimeric enzyme (ChiPFK) that contains the "rigid" ATP-binding domain of BsPFK grafted onto the remainder of the EcPFK subunit. Our results indicate that ChiPFK is locked in an "open" structure resembling the activated form of EcPFK. It is insensitive to heterotropic regulation. Nevertheless, ChiPFK exhibits residual cooperativity. Possible explanations for the cooperativity are discussed. The 6F loop is proposed to be important in PFK allosteric behavior. Residues along the loop are largely conserved between BsPFK and EcPFK, except for 161, which is a glutamate in BsPFK, and a glutamine in EcPFK. Using site-directed mutagenesis, Glu 161 of BsPFK has been changed to glutamine and alanine. Similarly, Gin 161 of EcPFK has been changed to glutamate, arginine and alanine. Of the five mutants, one, QA161, was particularly interesting. Though activated normally by GDP, it was completely insensitive to PEP inhibition. This indicates that the hydrogen-bonding ability of residue 161 is critical for PEP inhibition of EcPFK, and that GDP activation and PEP inhibition follow different structural pathways. (shrink)

The goal of this article is to show that formal analysis and reconstructions may be useful to discuss and shed light on substantive meta-theoretical issues. We proceed here by exemplification, analysing and reconstructing as a case study a paradigmatic biochemical theory, the Monod-Wyman-Changeux theory of allosterism, and applying the reconstruction to the discussion of some issues raised by prominent representatives of the new mechanist philosophy. We conclude that our study shows that at least in this case mechanicism and more traditional (...) accounts are not rivals but complementary approaches. (shrink)

Performance of bimanual motor actions requires coordinated and integrated bilateral communication, but in some bimanual tasks, neural interactions and crosstalk might cause bilateral interference. The level of interference probably depends on the proportions of bilateral interneurons connecting homologous areas of the motor cortex in the two hemispheres. The neuromuscular system for proximal muscles has a higher number of bilateral interneurons connecting homologous areas of the motor cortex compared to distal muscles. Based on the differences in neurophysiological organization for proximal vs. (...) distal effectors in the upper extremities, the purpose of the present experiment was to evaluate how the level of bilateral interference depends on whether the bilateral interference task is performed with homologous or non-homologous effectors as the primary task. Fourteen participants first performed a unilateral primary motor task with the dominant arm with proximal and distal controlled joysticks. Performance in the unilateral condition with the dominant arm was compared to the same effector’s performance when two different bilateral interference tasks were performed simultaneously with the non-dominant arm. The two different bilateral interference tasks were subdivided into homologous and non-homologous effectors. The results showed a significant decrease in performance for both proximal and distal controlled joysticks, and this effect was independent of whether the bilateral interference tasks were introduced with homologous or non-homologous effectors. The overall performance decrease as a result of bilateral interference was larger for proximal compared to distal controlled joysticks. Furthermore, a proximal bilateral interference caused a larger performance decrement independent of whether the primary motor task was controlled by a proximal or distal joystick. A novel finding was that the distal joystick performance equally interfered with either homologous or non-homologous interference tasks performed simultaneously. The results indicate that the proximal–distal distinction is an important organismic constraint on motor control and for understanding bilateral communication and interference in general and, in particular, how bilateral interference caused by homologous vs. non-homologous effectors impacts motor performance for proximal and distal effectors. The results seem to map neuroanatomical and neurophysiological differences for these effectors. (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)

Acute starvation can have long-term consequences that are mediated through epigenetic change. Some of these changes are affected by the activity of AMP-activated protein kinase, a master regulator of cellular energy homeostasis. In Caenorhabditis elegans, the absence of AMPK during a period of starvation in an early larval stage results in developmental defects following their recovery on food, while many of them become sterile. Moreover, the loss of AMPK during this quiescent period results in transgenerational phenotypes that can become progressively (...) worse with each successive generation. Our recent data describe a chromatin-based mechanism of how AMPK mediates adjustment to acute starvation in the germ cells, however, the heritable aspect of this AMPK mutant phenotype remains unresolved. Here, we explore how AMPK might affect this process and speculate how the initial transcription that occurs in the germ cells may adversely affect subsequent germline gene expression and/or genomic integrity. AMPK protects germ cell integrity during acute starvation by blocking inappropriate transcription. How these aberrant transcripts cause transgenerational defects is unclear. AMPK likely regulates germline integrity at multiple levels through several targets. The authors speculate here how AMPK disruption during starvation could result in the observed defects seen at each generation. (shrink)

The exact process that leads to the eruption of autoimmune reactions against β cells and the evolution of diabetes is not fully understood. Macrophages and T cells may launch an initial immune reaction against the pancreatic islets of Langerhans, provoking inflammation and destructive insulitis. The information on the molecular mechanisms of the emergence of β cell injury is controversial and points to possibly important roles for the perforin–granzyme, Fas–Fas-ligand (FasL) and tumor-necrosis-factor-mediated apoptotic pathways. FasL has several unique features that make (...) it a potentially ideal immunomodulatory tool. Most important, FasL is selectively toxic to cytotoxic T cells and less harmful to regulatory T cells. This review discusses the intrinsic sensitivity of β cells to FasL-mediated apoptosis, the conditions that underlie this β cell sensitivity, and the feasibility of using FasL to arrest autoimmunity and prevent islet allograft rejection. In both the autoimmune and transplant settings, it is imperative to progress from the administration of nonspecific immunosuppressive therapy to the concept of β-cell-specific immunomodulation. FasL evolves as a prime candidate for antigen-specific immunomodulation. BioEssays 28: 211–222, 2006. © 2006 Wiley periodicals, Inc. (shrink)

The exact process that leads to the eruption of autoimmune reactions against β cells and the evolution of diabetes is not fully understood. Macrophages and T cells may launch an initial immune reaction against the pancreatic islets of Langerhans, provoking inflammation and destructive insulitis. The information on the molecular mechanisms of the emergence of β cell injury is controversial and points to possibly important roles for the perforin–granzyme, Fas–Fas-ligand (FasL) and tumor-necrosis-factor-mediated apoptotic pathways. FasL has several unique features that make (...) it a potentially ideal immunomodulatory tool. Most important, FasL is selectively toxic to cytotoxic T cells and less harmful to regulatory T cells. This review discusses the intrinsic sensitivity of β cells to FasL-mediated apoptosis, the conditions that underlie this β cell sensitivity, and the feasibility of using FasL to arrest autoimmunity and prevent islet allograft rejection. In both the autoimmune and transplant settings, it is imperative to progress from the administration of nonspecific immunosuppressive therapy to the concept of β-cell-specific immunomodulation. FasL evolves as a prime candidate for antigen-specific immunomodulation. BioEssays 28: 211–222, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Cell signalling mediators derived from membrane phospholipids are frequent participants in biological processes. The family of phosphoinositide 3-kinases (PI3Ks) phosphorylate the membrane lipid phosphatidylinositol, generating second messengers that direct diverse responses. These PI3K products are fundamental for leukocyte migration or chemotaxis, a pivotal event during the immune response. This system is therefore of significant biomedical interest. This review focuses on the biochemistry and signalling pathways of PI3K, with particular emphasis on chemokine (chemotactic cytokine)-directed responses. The key objectives of chemotaxis are (...) motility and direction. The latter—direction—requires distinct events at the front and back of a cell. In light of this, the coordinated localisation of signalling factors, an event choreographed by a sharp intracellular gradient of PI3K-derived products, is a common theme. BioEssays 27:153–163, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Mitochondrial respiration is the predominant source of ATP. Excessive rates of electron transport cause a higher production of harmful reactive oxygen species (ROS). There are two regulatory mechanisms known. The first, according to Mitchel, is dependent on the mitochondrial membrane potential that drives ATP synthase for ATP production, and the second, the Kadenbach mechanism, is focussed on the binding of ATP to Cytochrome c Oxidase (CytOx) at high ATP/ADP ratios, which results in an allosteric conformational change to CytOx, causing (...) inhibition. In times of stress, ATP‐dependent inhibition is switched off and the activity of CytOx is exclusively determined by the membrane potential, leading to an increase in ROS production. The second mechanism for respiratory control depends on the quantity of electron transfer to the Heme aa3 of CytOx. When ATP is bound to CytOx the enzyme is inhibited, and ROS formation is decreased, although the mitochondrial membrane potential is increased. (shrink)

A new high‐resolution structure of a pain‐sensing ion channel, TRPA1, provides a molecular scaffold to understand channel function. Unexpected structural features include a TRP‐domain helix similar to TRPV1, a novel ligand‐binding site, and an unusual C‐terminal coiled coil stabilized by inositol hexakisphosphate (IP6). TRP‐domain helices, which structurally act as a nexus for communication between the channel gates and its other domains, may thus be a feature conserved across the entire TRP family and, possibly, other allosterically‐gated channels. Similarly, the TRPA1 antagonist‐binding (...) site could also represent a druggable location in other ion channels. Combined with known TRPA1 functional properties, the structural role for IP6 leads us to propose that polyphosphate unbinding could act as a molecular kill switch for TRPA1 inactivation. Finally, although packing of the TRPA1 membrane‐proximal region hints at a mechanism for electrophile sensing, the details of how TRPA1 responds to noxious reactive electrophiles and temperature await future studies.Also watch the Video Abstract. (shrink)

Phosphatidylinositol 4,5‐bisphosphate (PI4,5P2) is a key lipid signaling molecule that regulates a vast array of biological activities. PI4,5P2 can act directly as a messenger or can be utilized as a precursor to generate other messengers: inositol trisphosphate, diacylglycerol, or phosphatidylinositol 3,4,5‐trisphosphate. PI4,5P2 interacts with hundreds of different effector proteins. The enormous diversity of PI4,5P2 effector proteins and the spatio‐temporal control of PI4,5P2 generation allow PI4,5P2 signaling to control a broad spectrum of cellular functions. PI4,5P2 is synthesized by phosphatidylinositol phosphate kinases (...) (PIPKs). The array of PIPKs in cells enables their targeting to specific subcellular compartments through interactions with targeting factors that are often PI4,5P2 effectors. These interactions are a mechanism to define spatial and temporal PI4,5P2 synthesis and the specificity of PI4,5P2 signaling. In turn, the regulation of PI4,5P2 effectors at specific cellular compartments has implications for understanding how PI4,5P2 controls cellular processes and its role in diseases. (shrink)

The pore‐forming BCL‐2 family proteins are effectors of mitochondrial poration in apoptosis initiation. Two atypical effectors—BOK and truncated BID (tBID)—join the canonical effectors BAK and BAX. Gene knockout revealed developmental phenotypes in the absence the effectors, supporting their roles in vivo. During apoptosis effectors are activated and change shape from dormant monomers to dynamic oligomers that associate with and permeabilize mitochondria. BID is activated by proteolysis, BOK accumulates on inhibition of its degradation by the E3 (...) ligase gp78, while BAK and BAX undergo direct activation by BH3‐only initiators, autoactivation, and crossactivation. Except tBID, effector oligomers on the mitochondria appear as arcs and rings in super‐resolution microscopy images. The BH3‐in‐groove dimers of BAK and BAX, the tBID monomers, and uncharacterized BOK species are the putative building blocks of apoptotic pores. Effectors interact with lipids and bilayers but the mechanism of membrane poration remains elusive. I discuss effector‐mediated mitochondrial poration. (shrink)

Allosteric and transmembrane signaling are among the major questions of structural biology. Here, we review and discuss signal transduction in four-helical TM bundles, focusing on histidine kinases and chemoreceptors found in two-component systems. Previously, piston, scissors, and helical rotation have been proposed as the mechanisms of TM signaling. We discuss theoretically possible conformational changes and examine the available experimental data, including the recent crystallographic structures of nitrate/nitrite sensor histidine kinase NarQ and phototaxis system NpSRII:NpHtrII. We show that TM helices (...) can flex at multiple points and argue that the various conformational changes are not mutually exclusive, and often are observed concomitantly, throughout the TM domain or in its part. The piston and scissoring motions are the most prominent motions in the structures, but more research is needed for definitive conclusions. Models of allosteric transmembrane signaling in microbial sensor histidine kinases and chemoreceptors are discussed in light of recent crystallographic structures. It is shown that the TM α-helices are flexible and various conformational changes are often observed concomitantly. The piston and scissoring motions are the most prominent in the structures. (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)