Cardiac function modulation depends on the A‐kinase anchoring protein complex

The A‐kinase anchoring proteins (AKAPs) are a group of structurally diverse proteins identified in various species and tissues. These proteins are able to anchor protein kinase and other signalling proteins to regulate cardiac function. Acting as a scaffold protein, AKAPs ensure specificity in signal transduction by enzymes close to their appropriate effectors and substrates. Over the decades, more than 70 different AKAPs have been discovered. Accumulative evidence indicates that AKAPs play crucial roles in the functional regulation of cardiac diseases, including cardiac hypertrophy, myofibre contractility dysfunction and arrhythmias. By anchoring different partner proteins (PKA, PKC, PKD and LTCCs), AKAPs take part in different regulatory pathways to function as regulators in the heart, and a damaged structure can influence the activities of these complexes. In this review, we highlight recent advances in AKAP‐associated protein complexes, focusing on local signalling events that are perturbed in cardiac diseases and their roles in interacting with ion channels and their regulatory molecules. These new findings suggest that AKAPs might have potential therapeutic value in patients with cardiac diseases, particularly malignant rhythm.     

How regulators of G protein signaling achieve selective regulation

The regulators of G protein signaling (RGS) are a family of cellular proteins that play an essential regulatory role in G protein-mediated signal transduction. There are multiple RGS subfamilies consisting of over 20 different RGS proteins. They are basically the guanosine triphosphatase (GTPase)-accelerating proteins that specifically interact with G protein alpha subunits. RGS proteins display remarkable selectivity and specificity in their regulation of receptors, ion channels, and other G protein-mediated physiological events. The molecular and cellular mechanisms underlying such selectivity are complex and cooperate at many different levels. Recent research data have provided strong evidence that the spatiotemporal-specific expression of RGS proteins and their target components, as well as the specific protein-protein recognition and interaction through their characteristic structural domains and functional motifs, are determinants for RGS selectivity and specificity. Other molecular mechanisms, such as alternative splicing and scaffold proteins, also significantly contribute to RGS selectivity. To pursue a thorough understanding of the mechanisms of RGS selective regulation will be of great significance for the advancement of our knowledge of molecular and cellular signal transduction.     

The enigma of phosphoinositides and their derivatives: Their role in regulation of subcellular compartment morphology

The general segregation of a molecular class, lipids, from the pathways of cellular communication, via endo-membranes, has resulted in the over-simplification and misconceptions in deciphering cell signalling mechanisms. Mechanisms in signal transduction and protein activation require targeting of proteins to membranous compartments with a specific localised morphology and dynamics that are dependent on their lipid composition. Many posttranslational events define cellular behaviours and without the active role of membranous compartments these events lead to various dysregulations of the signalling pathways. We summarise the key findings, using tools such as the rapalogue dimerisation, in the structural roles and signalling of the inter-related phosphoinositide lipids and their derivative, diacylglycerol, in the regulation of nuclear envelope biogenesis and other subcellular compartments such as the nucleoplasmic reticulum.     

Protein-protein interactions in the membrane: sequence, structural, and biological motifs

Single-span transmembrane (TM) helices have structural and functional roles well beyond serving as mere anchors to tether water-soluble domains in the vicinity of the membrane. They frequently direct the assembly of protein complexes and mediate signal transduction in ways analogous to small modular domains in water-soluble proteins. This review highlights different sequence and structural motifs that direct TM assembly and discusses their roles in diverse biological processes. We believe that TM interactions are potential therapeutic targets, as evidenced by natural proteins that modulate other TM interactions and recent developments in the design of TM-targeting peptides.     

Positive and negative regulation of T-cell activation by adaptor proteins

Adaptor proteins, molecules that mediate intermolecular interactions, are now known to be as crucial for lymphocyte activation as are receptors and effectors. Extensive work from numerous laboratories has identified and characterized many of these adaptors, demonstrating their roles as both positive and negative regulators. Studies into the molecular basis for the actions of these molecules shows that they function in various ways, including: recruitment of positive or negative regulators into signalling networks, modulation of effector function by allosteric regulation of enzymatic activity, and by targeting other proteins for degradation. This review will focus on a number of adaptors that are important for lymphocyte function and emphasize the various ways in which these proteins carry out their essential roles.     

Signalling pathways in two-component phosphorelay systems

Two-component systems are characterized by phosphotransfer reactions involving histidine and aspartate residues in highly conserved signalling domains. Although the basic principles of signal transduction by these systems have been elucidated, several important aspects, such as their integration into more complex cellular regulatory networks and the molecular basis of the specificity of signal transduction, remain unknown.     

Insights into the PX (phox-homology) domain and SNX (sorting nexin) protein families: structures, functions and roles in disease

The mammalian genome encodes 49 proteins that possess a PX (phox-homology) domain, responsible for membrane attachment to organelles of the secretory and endocytic system via binding of phosphoinositide lipids. The PX domain proteins, most of which are classified as SNXs (sorting nexins), constitute an extremely diverse family of molecules that play varied roles in membrane trafficking, cell signalling, membrane remodelling and organelle motility. In the present review, we present an overview of the family, incorporating recent functional and structural insights, and propose an updated classification of the proteins into distinct subfamilies on the basis of these insights. Almost all PX domain proteins bind PtdIns3P and are recruited to early endosomal membranes. Although other specificities and localizations have been reported for a select few family members, the molecular basis for binding to other lipids is still not clear. The PX domain is also emerging as an important protein-protein interaction domain, binding endocytic and exocytic machinery, transmembrane proteins and many other molecules. A comprehensive survey of the molecular interactions governed by PX proteins highlights the functional diversity of the family as trafficking cargo adaptors and membrane-associated scaffolds regulating cell signalling. Finally, we examine the mounting evidence linking PX proteins to different disorders, in particular focusing on their emerging importance in both pathogen invasion and amyloid production in Alzheimer's disease.     

Secondary messengers and phospholipase A2 in auxin signal transduction

Despite recent progress auxin signal transduction remains largely scetchy and enigmatic. A good body of evidence supports the notion that the ABP1 could be a functional receptor or part of a receptor, respectively, but this is not generally accepted. Evidence for other functional receptors is lacking, as is any clearcut evidence for a function of G proteins. Protons may serve as second messengers in guard cells but the existing evidence for a role of calcium remains to be clearified. Phospholipases C and D seem not to have a function in auxin signal transduction whereas the indications for a role of phospholipase A₂ in auxin signal transduction accumulated recently. Mitogen-activated protein kinase (MAPK) is modulated by auxin and the protein kinase PINOID has a role in auxin transport modulation even though their functional linkage to other signalling molecules is ill-defined. It is hypothesized that signal transduction precedes activation of early genes such as IAA genes and that ubiquitination and the proteasome are a mechanism to integrate signal duration and signal strength in plants and act as major regulators of hormone sensitivity.     

Characterization of New Substrates Targeted By Yersinia Tyrosine Phosphatase YopH

YopH is an exceptionally active tyrosine phosphatase that is essential for virulence of Yersinia pestis, the bacterium causing plague. YopH breaks down signal transduction mechanisms in immune cells and inhibits the immune response. Only a few substrates for YopH have been characterized so far, for instance p130Cas and Fyb, but in view of YopH potency and the great number of proteins involved in signalling pathways it is quite likely that more proteins are substrates of this phosphatase. In this respect, we show here YopH interaction with several proteins not shown before, such as Gab1, Gab2, p85, and Vav and analyse the domains of YopH involved in these interactions. Furthermore, we show that Gab1, Gab2 and Vav are not dephosphorylated by YopH, in contrast to Fyb, Lck, or p85, which are readily dephosphorylated by the phosphatase. These data suggests that YopH might exert its actions by interacting with adaptors involved in signal transduction pathways, what allows the phosphatase to reach and dephosphorylate its susbstrates.     

A tale of two tails: cytosolic termini and K(+) channel function

The enormous variety of neuronal action potential waveforms can be ascribed, in large part, to the sculpting of their falling phases by currents through voltage-gated potassium channels. These proteins play several additional roles in other tissues such as the regulation of heartbeat and of insulin release from pancreatic cells as well as auditory signal processing in the cochlea. The functional channel is a tetramer with either six or two transmembrane segments per monomer. Selectivity filters, voltage sensors and gating elements have been mapped to residues within the transmembrane region. Cytoplasmic residues, which are accessible targets for signal transduction cascades and provide attractive means of regulation of channel activity, are now seen to be capable of modulating various aspects of channel function. Here we review structural studies on segments of the cytoplasmic tails of K⁺ channels, as well as the range of modulatory activities of these tails.     

Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins

The Toll/IL-1 receptor (TIR) domain plays a central role in Toll-like receptor (TLR) signalling. All TLRs contain a cytoplasmic TIR domain, which, upon activation, acts as a scaffold to recruit adaptor proteins. The adaptor proteins MyD88, Mal, TRIF, TRAM and SARM are also characterized by the presence of a TIR domain. MyD88, Mal, TRIF and TRAM associate with the TLRs via homophilic TIR domain interactions whereas SARM utilizes its TIR domain to negatively regulate TRIF. It is well established that the differential recruitment of adaptors to TLRs provides a significant amount of specificity to the TLR-signalling pathways. Despite this, the TIR-TIR interface has not been well defined. However, structural studies have indicated the importance of TIR domain surfaces in mediating specific TIR-TIR interactions. Furthermore, recent findings regarding the regulation of adaptors provide further insight into the crucial role of the TIR domain in TLR signalling.     

Between genotype and phenotype: protein chaperones and evolvability

Protein chaperones direct the folding of polypeptides into functional proteins, facilitate developmental signalling and, as heat-shock proteins (HSPs), can be indispensable for survival in unpredictable environments. Recent work shows that the main HSP chaperone families also buffer phenotypic variation. Chaperones can do this either directly through masking the phenotypic effects of mutant polypeptides by allowing their correct folding, or indirectly through buffering the expression of morphogenic variation in threshold traits by regulating signal transduction. Environmentally sensitive chaperone functions in protein folding and signal transduction have different potential consequences for the evolution of populations and lineages under selection in changing environments.     

Mutations in signal transduction pathways and inherited diseases.

Intracellular signal transduction pathways have central roles in processes such as growth, differentiation, neurotransmission and development. The aberrant expression of components of various signal transduction pathways has profound consequences for cellular functions. Recent findings indicate that many cases of neoplasia and inherited diseases have, at their roots, mutations in key steps of signalling pathways.