Cullin‐RING ligases (CRLs) are central regulators of environmental and cellular stress responses, orchestrating diverse processes through the ubiquitination of substrate proteins. As modular complexes, CRLs employ substrate‐specific adaptors to target proteins for degradation and other ubiquitin‐mediated processes, enabling dynamic adaptation to environmental cues. Recent advances have highlighted the largest CRL subfamily SCF (Skp1‐cullin‐F‐box) in environmental sensing, a role historically underappreciated for SCF ubiquitin ligases. Notably, emerging evidence suggests that the F‐box domain, a 50‐amino acid motif traditionally recognized for mediating (...) class='Hi'>protein‐protein interactions, can act as a direct environmental sensor due to its ability to bind heavy metals. Despite these advances, the roles of many CRL components in environmental sensing remain poorly understood. This review provides an overview of CRLs in stress response regulation and emphasizes the emerging functions of F‐box proteins in environmental adaptation. (shrink)

The multistep pathway of eukaryotic gene expression involves a series of highly regulated events in the nucleus and cytoplasm. In the nucleus, genes are transcribed into pre‐messenger RNAs which undergo a series of nuclear processing steps. Mature mRNAs are then transported to the cytoplasm, where they are translated into protein and degraded at a rate dictated by transcript‐ and cell‐type‐specific cues. Until recently, these individual nuclear and cytoplasmic events were thought to be primarily regulated by different RNA‐ and DNA‐binding (...) proteins that are localized either only in the nucleus or only the cytoplasm. Here, we describe multifunctional proteins that control both nuclear and cytoplasmic steps of gene expression. One such class of multifunctional proteins (e.g., Bicoid and Y‐box proteins) regulates both transcription and translation whereas another class (e.g., Sex‐lethal) regulates both nuclear RNA processing and translation. Other events controlled by multifunctional proteins include assembly of spliceosome components, spliceosome recycling, RNA editing, cytoplasmic mRNA localization, and cytoplasmic RNA stability. The existence of multifunctional proteins may explain the paradoxical involvement of the nucleus in an RNA surveillance pathway (nonsense‐mediated decay) that detects cytoplasmic signals (premature termination codons). We speculate that shuttling multifunctional proteins serve to efficiently link RNA metabolism in the cytoplasmic and nuclear compartments. BioEssays 23:775–787, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Back‐to‐back papers have described the identification of a family of receptors for the plant hormone auxin.(1, 2) Most developmental processes in plants are dependent on auxin signalling making this discovery a landmark in the search for the mechanism of auxin action. The TIR1 gene translates into a protein with recognised motifs including an F‐box domain and TIR1 forms part of an important ubiquitination complex that tags other proteins for degradation.(3) Specific amongst the targets of TIR1 are a set of (...) auxin‐regulated transcription factors.(4) The latest work has shown that TIR1 itself is also the binding site for auxin making it an auxin receptor with no requirement for a biochemical signalling cascade. BioEssays 27:1213–1217, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Members of the Y‐box (YB) family of transcription factors are expressed in a wide range of cell types and are implicated in the regulation of a rapidly increasing number of genes. Although the biological activities of YB proteins appear to be varied, distinct patterns, relating to the timing of their expression and the identity of their target genes, are beginning to emerge. A recent report by Ito et al.(1) focusses attention on cell proliferation and adds support to earlier suggestions(2, 3) (...) that a primary function of YB proteins is to help activate growth‐associated genes. (shrink)

Peroxisomal matrix proteins are synthesized on cytosolic ribosomes and rapidly transported into the organelle by a complex machinery. The data gathered in recent years suggest that this machinery operates through a syringe-like mechanism, in which the shuttling receptor PEX5 − the “plunger” − pushes a newly synthesized protein all the way through a peroxisomal transmembrane protein complex − the “barrel” − into the matrix of the organelle. Notably, insertion of cargo-loaded receptor into the “barrel” is an ATP-independent process, (...) whereas extraction of the receptor back into the cytosol requires its monoubiquitination and the action of ATP-dependent mechanoenzymes. Here, we review the main data behind this model. The peroxin PEX5 is the peroxisomal matrix protein receptor. It shuttles between the cytosol and the organelle membrane, where it gets inserted into the docking/translocation module, thus pushing the cargo-protein into the peroxisome lumen. Resetting the system involves PEX5 monoubiquitination and its extraction from the membrane by the AAA-ATPases, PEX1/PEX6. (shrink)

Although higher-level constructs often fail to explain the mechanisms underlying motivation, we argue that purely mechanistic approaches have limitations. Lower-level neural data help us identify “biologically plausible” mechanisms, while higher-level constructs are critical to formulate measurable behavioral outcomes when constructing computational models. Therefore, we propose that a multi-level, multi-measure approach is required to fully unpack the black box of motivated behavior.

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.

This review will discuss how STAT (Signal Transducers and Activators of Transcription) proteins, a group of transcription factors that transmit signals from the extracellular surface of cells to the nucleus, are involved in growth control. I will discuss the anatomy of a STAT protein, how it works as a transcription factor, the molecules that regulate its “activity”, the phenotypes of mice that lack individual STAT proteins and their involvement in growth, differentiation, apoptosis, and transformation. Finally, a number of examples (...) will be presented of how dysregulated STAT signaling may be involved in the pathogenesis of cancer. BioEssays 23:161–169, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Much progress has been made in recent years regarding the mechanisms of targeting of secretory proteins to, and across, the endoplasmic reticulum (ER) membrane. Many of the cellular components involved in mediating translocation across this bilayer have been identified and characterized. Polypeptide domains of secretory proteins, termed signal peptides, have been shown to be necessary, and in most cases sufficient, for entry of preproteins into the lumen of the ER. These NH2‐ terminal segments appear to serve multiple roles in targeting (...) and translocation. The structural features which mediate their multiple functions are currently the subject of intense study. (shrink)

It has long been observed that human protein‐coding genes have a particular distribution of GC‐content: the 5′ end of these genes has high GC‐content while the 3′ end has low GC‐content. In 2012, it was proposed that this pattern of GC‐content could act as an mRNA identity feature that would lead to it being better recognized by the cellular machinery to promote its nuclear export. In contrast, junk RNA, which largely lacks this feature, would be retained in the nucleus (...) and targeted for decay. Now two recent papers have provided evidence that GC‐content does promote the nuclear export of many mRNAs in human cells. (shrink)

Open peer commentary on the article ““Black Box” Theatre: Second-Order Cybernetics and Naturalism in Rehearsal and Performance” by Tom Scholte. Upshot: What von Foerster accomplished in raising the specter of second-order cybernetics now requires experimental design and the heavy lifting of theory to complete his quest for new ways of thinking. Scholte’s “black box theatre” points to research into non-trivial systems as a formal means of grasping living systems.

The most enigmatic feature of polytene chromosomes is their banding pattern, the genetic organization of which has been a very attractive puzzle for many years. Recent genome‐wide protein mapping efforts have produced a wealth of data for the chromosome proteins of Drosophila cells. Based on their specific protein composition, the chromosomes comprise two types of bands, as well as interbands. These differ in terms of time of replication and specific types of proteins. The interbands are characterized by their (...) association with “active” chromatin proteins, nucleosome remodeling, and origin recognition complexes, and so they have three functions: acting as binding sites for RNA pol II, initiation of replication and nucleosome remodeling of short fragments of DNA. The borders and organization of the same band and interband regions are largely identical, irrespective of the cell type studied. This demonstrates that the banding pattern is a universal principle of the organization of interphase polytene and non‐polytene chromosomes.Editor's suggested further reading in BioEssaysCaught in the act: Rapid, symbiont‐driven evolution AbstractFunction and evolution of sex determination mechanisms, genes and pathways in insects Abstract. (shrink)

The Y‐box proteins are the most evolutionarily conserved nucleic acid binding proteins yet defined in bacteria, plants and animals. The central nucleic acid binding domain of the vertebrate proteins is 43% identical to a 70‐amino‐acid‐long protein (CS7.4) from E. coli. The structure of this domain consists of an antiparallel fivestranded β‐barrel that recognizes both DNA and RNA. The diverse biological roles of these Y‐box proteins range from the control of the E. coli cold‐shock stress response to the translational masking (...) of messenger RNA in vertebrate gametes. This review discusses the organization of the prokaryotic and eukaryotic Y‐box proteins, how they interact with nucleic acids, and their biological roles, both proven and potential. (shrink)

The mitochondrion is known as the “powerhouse” of eukaryotic cells since it is the main site of adenosine 5′‐triphosphate (ATP) production. Using a temperature‐sensitive fluorescent probe, it has recently been suggested that the stray free energy, not captured into ATP, is potentially sufficient to sustain mitochondrial temperatures higher than the cellular environment, possibly reaching up to 50 °C. By 50 °C, some DNA and mitochondrial proteins may reach their melting temperatures; how then do these biomolecules maintain their structure and function? (...) Further, the production of reactive oxygen species (ROS) accelerates with temperature, implying higher oxidative stresses in the mitochondrion than generally appreciated. Herein, it is proposed that mitochondrial heat shock proteins (particularly Hsp70), in addition to their roles in protein transport and folding, protect mitochondrial proteins and DNA from thermal and ROS damage. Other thermoprotectant mechanisms are also discussed. (shrink)

One of the central issue of developmental biology concerns the molecular mechanisms whereby a multipotent cell gives rise to distinct differentiated progeny. Differences between specialised cell types reflect variations in their patterns of gene expression. The regulation of transcription initiation is an important control point for gene expression and it is, therefore, not surprising that transcription factors play a pivotal role in mammalian development and differentiation.Haemopoiesis offers a uniquely tractable system for the study of lineage commitment and differentiation. The importance (...) of transcription factor in the normal regulation of haemopoiesis is underlined by the frequency with which transcription factors are targeted by leukaemogenic mutations. Studies of the function and regulation of haemopoietic transcription factors, especially those expressed in lineage‐restricted patterns, should greatly increase our understanding of the molecular control of haemopoiesis. In this review we have focused on insights provided by recent studies of the GATA and SCL proteins. (shrink)

Mature rats were kept on protein-deficient diets to test the hypothesis that late-onset protein restriction results in deficits and to determine the feasibility of doing nutrition-behavior research with old naive animals. A 3% low-protein (LP) group and a 24% adequate-protein (AP) pair-fed control were used. Body weights and plasma protein concentrations were lower and exploratory behavior and motor coordination were poorer for LP rats. Both groups preferred the 24% protein diet. LP rats habituated slower (...) and failed to overcome an initial black preference on an oddity discrimination learning task. Nutrition-behavioral research with older rats is feasible, and late-onset protein restriction produces psychobiological deficits. (shrink)

Hereditary retinal degeneration due to mutations in visual genes may be amenable to therapeutic interventions that modulate, either positively or negatively, the amount of protein product. Some of the proteins involved in phototransduction are rapidly moved by a lightdependent mechanism between the inner segment and the outer segment in rod photoreceptor cells, and this phenomenon is important in phototransduction.

Cytokine receptors fall into two basic classes: those with their own intrinsic protein tyrosine kinase (PTK) domain, and those lacking a PTK domain. Nonetheless, PTK activity plays a fundamental role in the signal transduction processes lying downstream of both classes of receptor. It now seems likely that many of those cytokine receptors that lack their own PTK domain use members of the JAK family of PTKs to propagate their intracellular signals. Moreover, the involvement of the JAK kinases in a (...) newly defined pathway which links membrane receptors directly to the activation of nuclear genes, via latent cytoplasmic transcription factors known as STATs (for Signal Transducers and Activators of Transcription), appears to be a theme common to cytokine receptors of both classes. (shrink)

Twenty five years ago, Sir John Carew Eccles together with Friedrich Beck proposed a quantum mechanical model of neurotransmitter release at synapses in the human cerebral cortex. The model endorsed causal influence of human consciousness upon the functioning of synapses in the brain through quantum tunneling of unidentified quasiparticles that trigger the exocytosis of synaptic vesicles, thereby initiating the transmission of information from the presynaptic towards the postsynaptic neuron. Here, we provide a molecular upgrade of the Beck and Eccles model (...) by identifying the quantum quasiparticles as Davydov solitons that twist the protein α-helices and trigger exocytosis of synaptic vesicles through helical zipping of the SNARE protein complex. We also calculate the observable probabilities for exocytosis based on the mass of this quasiparticle, along with the characteristics of the potential energy barrier through which tunneling is necessary. We further review the current experimental evidence in support of this novel bio-molecular model as presented. (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)

In the beginning of the 20th century the groundbreaking work of Ramon y Cajal firmly established the neuron doctrine, according to which neurons are the basic structural and functional units of the nervous system. Von Weldeyer coined the term “neuron” in 1891, but the huge leap forward in neuroscience was due to Cajal’s meticulous microscopic observations of brain sections stained with an improved version of Golgi’s la reazione nera (black reaction). The latter improvement of Golgi’s technique made it possible to (...) visualize the arborizations of single neurons that were “colored brownish black even to their finest branchlets, standing out with unsurpassable clarity upon a transparent yellow background. All was sharp as a sketch with Chinese ink”. The high quality of both the visualization of individual nerve cells and the work performed on studying the anatomy of the central nervous system lead Ramon y Cajal to the conclusion that axons output the nervous impulses to the dendrites or the soma of other target neurons. (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)

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)

G protein‐coupled receptors (GPCRs) constitute the largest family of transmembrane proteins and play a crucial role in regulating diverse cellular functions. They transmit their signaling via binding to intracellular signal transducers and effectors, such as G proteins, GPCR kinases, and β‐arrestins. To influence specific GPCR signaling behaviors, β‐arrestins recruit effectors to form larger signaling complexes. Intriguingly, they facilitate divergent functions for the binding to different receptors. Recent studies relying on advanced structural approaches, novel biosensors and interactome analyses bring us (...) closer to understanding how this specificity is achieved. In this article, we share our hypothesis of how active GPCRs induce specific conformational rearrangements within β‐arrestins to reveal distinct binding interfaces, enabling the recruitment of a subset of effectors to foster specialized signaling complexes. Furthermore, we discuss methods of how to comprehensively assess β‐arrestin conformational states and present the current state of research regarding the functionality of these multifaceted scaffolding proteins. (shrink)

A diverse group of DNA‐binding regulatory proteins share a common structural domain which is homologous to the sequence of a highly conserved and abundant chromosomal protein, HMG‐1. Proteins containing this HMG‐1 box regulate various cellular functions involving DNA binding, suggesting that the target DNA sequences share a common structural element. Members of this protein family exhibit a dual DNA‐binding specificity: each recognizes a unique sequence as well as a common DNA conformation. The highly conserved HMG‐1/‐2 proteins may modulate (...) the binding of other HMG‐1 box proteins to bent DNA. We examine the structural and functional relationships between the proteins, identify their signature† and describe common features of their target DNA elements. (shrink)

The Hippo pathway, a cascade of protein kinases that inhibits the oncogenic transcriptional coactivators YAP and TAZ, was discovered in Drosophila as a major determinant of organ size in development. Known modes of regulation involve surface proteins that mediate cell‐cell contact or determine epithelial cell polarity which, in a tissue‐specific manner, use intracellular complexes containing FERM domain and actin‐binding proteins to modulate the kinase activities or directly sequester YAP. Unexpectedly, recent work demonstrates that GPCRs, especially those signaling through Galpha12/13 (...) such as the protease activated receptor PAR1, cause potent YAP dephosphorylation and activation. This response requires active RhoA GTPase and increased assembly of filamentous (F‐)actin. Morever, cell architectures that promote F‐actin assembly per se also activate YAP by kinase‐dependent and independent mechanisms. These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells. (shrink)

Protein‐carbohydrate interactions have been found to be important in many steps in lymphocyte recirculation and inflammatory responses. A family of carbohydrate‐binding proteins or lectins, termed selectins, has been discovered and shown to be involved directly in these processes. The three known selectins, termed L‐, E‐ and P‐selectins, have domains homologous to other Ca2+‐dependent (C‐type) lectins. L‐selectin is expressed constitutively on lymphocytes, E‐selectin is expressed by activated endothelial cells, and P‐selectin is expressed by activated platelets and endothelial cells. Here, we (...) review the nature of the carbohydrate determinants in tissues recognized by these selectins. The expression of specific sialylated, fucosylated and sulfated carbohydrates in activated endothelium and high endothelial venules promotes interactions with L‐selectin on leukocyte surfaces. In contrast, E‐ and P‐selectins recognize specific carbohydrate determinants related to sialyl Lex antigen on neutrophil and monocyte surfaces. The discovery of the selectins has generated excitemient among glycoconjugate researchers that other carbohydrate‐binding proteins and their cognate ligands will be found to function in regulating many types of cellular interactions. (shrink)

The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Feng et al. now report a new function for UPF1—it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro-muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to (...) define other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. The RNA-binding protein, UPF1, is best known for its central role in the nonsense-mediated RNA decay pathway. Here we discuss a new role for UPF1—it is directly involved in protein decay. This hidden talent raises the possibility that protein turnover and RNA turnover are coupled processes. (shrink)