Histidine kinases and response regulator proteins in two-component signaling systems.

Phosphotransfer-mediated signaling pathways allow cells to sense and respond to environmental stimuli. Autophosphorylating histidine protein kinases provide phosphoryl groups for response regulator proteins which, in turn, function as molecular switches that control diverse effector activities. Structural studies of proteins involved in two-component signaling systems have revealed a modular architecture with versatile conserved domains that are readily adapted to the specific needs of individual systems.     

Potassium channels: life in the post-structural world

More than three years have passed since the first structure of a potassium channel protein revealed fundamental molecular details of a platform for ion-selective conduction. Recent efforts have turned to understanding what this structure tells us about potassium channel structure and function in general and, most importantly, which questions remain unanswered. Successes in solving membrane protein structures are still hard won and slow. High-resolution studies of cytoplasmic channel domains and channel-associated proteins, the most tractable entry points for dissecting large, complex eukaryotic channels, are revealing a modularity of function commonly seen in many other biological systems. Studies of these domains bring into sharp focus issues of channel regulation, how these domains and associated proteins are coupled to the transmembrane domains to influence channel function, and how ion channels are integrated into cellular signaling pathways.     

A tale of two components: a novel kinase and a regulatory switch

Histidine protein kinases and response regulators form the basis of phosphotransfer signal transduction pathways. Commonly referred to as two-component systems, these modular and adaptable signaling schemes are prevalent in prokaryotes. Structures of the core domains of histidine kinases reveal a protein kinase fold different from that of the Ser/Thr/Tyr protein kinase family, but similar to that of other ATP binding domains. Recent structure determinations of phosphorylated response regulator domains indicate a conserved mechanism for the propagated conformational change that accompanies phosphorylation of an active site Asp residue. The altered molecular surface promotes specific protein-protein interactions that mediate the downstream response.     

p62蛋白的分子功能及其在疾病中的研究进展

螯合体1(SQSTM1/p62)是一种选择性自噬接头蛋白,在清除待降解蛋白、维持细胞内蛋白质稳态中发挥重要的调控作用。p62蛋白具有多个功能结构域,介导与多种蛋白质发生相互作用进而精确调节特定的信号通路,从而将p62蛋白与氧化防御系统、炎症反应和营养感知等重要生命过程联系起来。研究表明p62的突变或者表达异常与多种疾病的发生发展过程密切相关,包括神经退行性疾病、肿瘤、感染性疾病、遗传性疾病以及慢性疾病等。本文综述了p62蛋白的结构特征、分子功能,并系统介绍其在蛋白质稳态和信号通路调控中的多种功能,总结了p62在疾病发生发展中的复杂性与多面性,以期为p62蛋白的功能与相关疾病研究提供参考。     

Signal transduction systems in prokaryotes

The main components of chemosignaling systems of prokaryotes are multifunctional receptor molecules that include both sensor domains specifically recognizing external signals and effector domains converting these signals into an adequate cell response. This review summarizes and analyzes data on structural-functional organization, molecular mechanisms of action, and regulation of receptor forms of histidine kinases, adenylyl kinases, diguanylyl cyclases, and phosphodiesterases. These enzymes have been shown to be precursors of the receptor and effector components of the eukaryote hormonal signaling systems. This confirms the hypothesis developed by the authors about formation of the main archetypes of chemosignaling systems at the early evolution stages and about the evolutionary relationship of the signaling systems of prokaryotes and eukaryotes.     

Signal transduction systems of prokaryotes

The main components of chemosignaling systems of prokaryotes are multifunctional receptor molecules that include both sensor domains specifically recognizing external signals and effector domains converting these signals into an adequate cell response. This review summarizes and analyzes data of structural-functional organization, molecular mechanisms of action, and regulation of receptor forms of histidine kinases, adenylyl cyclases, diguanylyl cyclases, and phosphodiesterases. These enzymes have been shown to be precursors of the receptor and effector components of the eukaryote hormonal signaling systems. This confirms the hypothesis developed by the authors about formation of the main archetypes of chemosignaling systems at the early evolution stages and about the evolutionary relationship of the signaling systems of prokaryotes and eukaryotes.     

PDZ domains - common players in the cell signaling

PDZ domains are ubiquitous protein interaction modules that play a key role in cellular signaling. Their binding specificity involves recognition of the carboxyl-terminus of various proteins, often belonging to receptor and ion channel families. PDZ domains also mediate more complicated molecular networks through PDZ-PDZ interactions, recognition of internal protein sequences or phosphatidylinositol moieties. The domains often form a tandem of multiple copies, but equally often such tandems or single PDZ domain occur in combination with other signaling domains (for example SH3, DH/PH, GUK, LIM, CaMK). Common occurrence of PDZ domains in Metazoans strongly suggests that their evolutionary appearance results from the complication of signaling mechanisms in multicellular organisms. Here, we focus on their structure, specificity and role in signaling pathways.     

Posttranslational protein S-palmitoylation and the compartmentalization of signaling molecules in neurons

Protein domains play a fundamental role in the spatial and temporal organization of intracellular signaling systems. While protein phosphorylation has long been known to modify the interactions that underlie this organization, the dynamic cycling of lipids should now be included amongst the posttranslational processes determining specificity in signal transduction. The characteristics of this process are reminiscent of the properties of protein and lipid phosphorylation in determining compartmentalization through SH2 or PH domains. Recent studies have confirmed the functional importance of protein S-palmitoylation in the compartmentalization of signaling molecules that support normal physiological function in cell division and apoptosis, and synaptic transmission and neurite outgrowth. In neurons, S-palmitoylation and targeting of proteins to rafts are regulated differentially in development by a number of processes, including some related to synaptogenesis and synaptic plasticity. Alterations in the S-palmitoylation state of proteins substantially affect their cellular function, raising the possibility of new therapeutic targets in cancer and nervous system injury and disease.     

Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems

Over the last two decades, a new and unifying concept of cellular organization has emerged in which modular protein-protein interactions provide an underlying framework through which signaling pathways are assembled and controlled. In this scheme, posttranslational modifications such as phosphorylation commonly exert their biological effects by regulating molecular interactions, exemplified by the ability of phosphotyrosine sites to bind selectively to SH2 domains. Although these interactions are rather simple in isolation, they can nonetheless be exploited to generate complex cellular systems. Here, I discuss experiments that have led to this view of dynamic cellular behavior and identify some current and future areas of interest in cell signaling.     

Cellular mechanisms of signal transduction for neurotrophins

The molecular cloning of new neuroactive growth factors and their receptors has greatly enhanced our understanding of important interactions among receptors and singnaling molecules. These studies have begun to illuminate some of the mechanisms that allow for specificity in neuronal signaling. Model cell systems, such as the PC-12 pheochromocytoma cell line, express receptors for these different neurotirophic factors, leading to comparisons of signaling pathways for these factors. Upon binding their ligands, these receptors undergo phosphorylation on tyrosine residues, which directs their interaction with signaling proteins containing src homology (SH2) domains, sequences that mediate associations with tyrosine-phosphorylated proteins. These SH2 proteins translate the tyrosine kinase activity of receptors into downstream events that result in the specific cellular response. Investigations such as these have revealed that molecular specificity in signaling pathways may arise from combinatorial diversity in interactions between receptors and key regulatory proteins.     

Uncovering new aspects of protein interactions through analysis of specificity landscapes in peptide recognition domains

Protein interactions underlie all biological processes. An important class of protein interactions, often observed in signaling pathways, consists of peptide recognition domains binding short protein segments on the surface of their target proteins. Recent developments in experimental techniques have uncovered many such interactions and shed new lights on their specificity. To analyze these data, novel computational methods have been introduced that can accurately describe the specificity landscape of peptide recognition domains and predict new interactions. Combining large-scale analysis of binding specificity data with structure-based modeling can further reveal new biological insights into the molecular recognition events underlying signaling pathways.     

WW and SH3 domains, two different scaffolds to recognize proline-rich ligands

WW domains are small protein modules composed of approximately 40 amino acids. These domains fold as a stable, triple stranded beta-sheet and recognize proline-containing ligands. WW domains are found in many different signaling and structural proteins, often localized in the cytoplasm as well as in the cell nucleus. Based on analyses of seven structures of WW domains, we discuss their diverse binding preferences and sequence conservation patterns. While modeling WW domains for which structures have not been determined we uncovered a case of potential molecular and functional convergence between WW and SH3 domains. The binding surface of the modeled WW domain of Npw38 protein shows a remarkable similarity to the SH3 domain of Sem5 protein, confirming biochemical data on similar binding predilections of both domains.     

Elucidating structural and molecular mechanisms of β-arrestin-biased agonism at GPCRs via MS-based proteomics

The discovery of β-arrestin-dependent GPCR signaling has led to an exciting new field in GPCR pharmacology: to develop “biased agonists” that can selectively target a specific downstream signaling pathway that elicits beneficial therapeutic effects without activating other pathways that elicit negative side effects. This new trend in GPCR drug discovery requires us to understand the structural and molecular mechanisms of β-arrestin-biased agonism, which largely remain unclear. We have used cutting-edge mass spectrometry (MS)-based proteomics, combined with systems, chemical and structural biology to study protein function, macromolecular interaction, protein expression and posttranslational modifications in the β-arrestin-dependent GPCR signaling. These high-throughput proteomic studies have provided a systems view of β-arrestin-biased agonism from several perspectives: distinct receptor phosphorylation barcode, multiple receptor conformations, distinct β-arrestin conformations, and ligand-specific signaling. The information obtained from these studies offers new insights into the molecular basis of GPCR regulation by β-arrestin and provides a potential platform for developing novel therapeutic interventions through GPCRs.     

Activation of RIG-I-like receptor signal transduction

Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral response. Pattern recognition receptor proteins detect molecular signatures of virus infection and activate antiviral signaling cascades. The RIG-I-like receptors are cytoplasmic DExD/H box proteins that can specifically recognize virus-derived RNA species as a molecular feature discriminating the pathogen from the host. The RIG-I-like receptor family is composed of three homologous proteins, RIG-I, MDA5, and LGP2. All of these proteins can bind double-stranded RNA species with varying affinities via their conserved DExD/H box RNA helicase domains and C-terminal regulatory domains. The recognition of foreign RNA by the RLRs activates enzymatic functions and initiates signal transduction pathways resulting in the production of antiviral cytokines and the establishment of a broadly effective cellular antiviral state that protects neighboring cells from infection and triggers innate and adaptive immune systems. The propagation of this signal via the interferon antiviral system has been studied extensively, while the precise roles for enzymatic activities of the RNA helicase domain in antiviral responses are only beginning to be elucidated. Here, current models for RLR ligand recognition and signaling are reviewed.     

Activation of RIG-I-like receptor signal transduction

Mammalian cells have the ability to recognize virus infection and mount a powerful antiviral response. Pattern recognition receptor proteins detect molecular signatures of virus infection and activate antiviral signaling cascades. The RIG-I-like receptors are cytoplasmic DExD/H box proteins that can specifically recognize virus-derived RNA species as a molecular feature discriminating the pathogen from the host. The RIG-I-like receptor family is composed of three homologous proteins, RIG-I, MDA5, and LGP2. All of these proteins can bind double-stranded RNA species with varying affinities via their conserved DExD/H box RNA helicase domains and C-terminal regulatory domains. The recognition of foreign RNA by the RLRs activates enzymatic functions and initiates signal transduction pathways resulting in the production of antiviral cytokines and the establishment of a broadly effective cellular antiviral state that protects neighboring cells from infection and triggers innate and adaptive immune systems. The propagation of this signal via the interferon antiviral system has been studied extensively, while the precise roles for enzymatic activities of the RNA helicase domain in antiviral responses are only beginning to be elucidated. Here, current models for RLR ligand recognition and signaling are reviewed.