Cells diversify transmembrane signaling through the controlled chaos of protein disorder

Abstract

C ell surface receptors function to transduce signals across the cell membrane leading to a variety of biologic responses. Structurally, these integral proteins can be classified into two main families, depending on whether extracellular ligand-binding and intracellular signaling domains are located on the same protein chain (single-chain receptors, SRs) or on separate subunits (multichain receptors, MRs). Since most MRs are immune receptors, they are all commonly referred to as multichain immune recognition receptors (MIRRs). Recent studies reveal that, in contrast to well-structured signaling domains of SRs, those of MIRRs represent intrinsically disordered regions, the regions that lack a well-defined threedimensional structure under physiological conditions. Why did nature separate recognition and signaling functions of MIRRs? Why for MIRRs did nature select to provide highly specific signaling through the chaos of protein disorder? What mechanisms could control this chaos in the process of transmembrane signal transduction to provide the specificity and diversity of the immune response? Here, I summarize recent findings that may not only shed light on these and other questions but also add significantly to our understanding of receptor signaling, a fundamental process that plays a critical role in health and disease.

Targeting Intramembrane Protein–Protein Interactions: Novel Therapeutic Strategy of Millions Years Old

“…Another observation is that while extracellular (ligand recognition), transmembrane and cytoplasmic (signaling) domains of SRs are all well structured (Sigalov, 2010c(Sigalov, , 2011a(Sigalov, , 2012b, cytoplasmic domains of MIRR signaling subunits are all intrinsically disordered (i.e., these domains lack a well-defined ordered structure under physiological conditions in vitro) in contrast to the well-structured MIRR extracellular (ligand recognition) and transmembrane domains (Sigalov, 2011a(Sigalov, , 2011c(Sigalov, , 2012bSigalov et al, 2004Sigalov et al, , 2007Sigalov, Aivazian, Uversky, & Stern, 2006). Ultimately, these observations raise two intriguing questions (Sigalov, 2011a(Sigalov, , 2012a. First, why did nature separate recognition and signaling functions for MIRRs, thereby increasing the risk of malfunction and potential attack by pathogens, and second, why did nature select protein disorder for MIRRs to translate recognition of distinct ligands into appropriate activation signals that would induce distinct specific functional outcomes ( Fig.…”

“…2)? Answering the first question, one can suggest that the modular assembly of MIRRs brings multiple benefits the most important of which is the capability to diversify and vary signal transduction (Sigalov, 2010c(Sigalov, , 2010d(Sigalov, , 2011b(Sigalov, , 2012a. Ultimately, this provides the mechanistic basis for Fig.…”

“…In the context of immune signaling, this is of great importance in the development and evolution of the immune defense. Protein disorder contributes to the diversity and variability of signal transduction without compromising efficiency and specificity of signaling (Sigalov, 2010c(Sigalov, , 2010d(Sigalov, , 2011b(Sigalov, , 2012a(Sigalov, , 2012b. Thus, evolutionary and developmental benefits of immune signaling-related protein disorder outweigh attendant disadvantages which are largely compensated for by increasing the host defense.…”

“…3). Importantly, functions of the ITAM modules, including those located on different ( Jensen et al, 1997;Pike et al, 2004;Pitcher & van Oers, 2003;Sanchez-Mejorada & Rosales, 1998;Sigalov, 2004Sigalov, , 2006Sigalov, , 2010cSigalov, , 2011aSigalov, , 2012b or the same (e.g., three different ITAMs on the ζ chain) (Chae et al, 2004) signaling chains and those located on the same chain are rather distinct instead of redundant. This provides a molecular explanation for significantly higher diversity and variability of the adaptive response as compared to the innate response.…”

Βιοπληροφορικές Μελέτες Δομής Και Λειτουργίας Μεμβρανικών Πρωτεϊνών

“…Επιπλέον, σε πολλές περιπτώσεις, οι πρωτεΐνες αποκτούν συγκεκριμένη και σταθερή τρισδιάστατη δομή μετά την αλληλεπίδραση τους με κάποιο συγκεκριμένο στόχο, πιθανόν επιτρέποντας με τον τρόπο αυτό τη ρύθμιση διαφόρων κυτταρικών διεργασιών όπως η ρύθμιση της μεταγραφής και μετάφρασης και ο έλεγχος του κυτταρικού κύκλου. Sigalov, 2011;Stavropoulos et al, 2012;Xue et al, 2009a (Gnad et al, 2007;Landry et al, 2009;Malik et al, 2008;Zhao et al, 2012 (Dunker et al, 2002a;Dunker et al, 2002b;Iakoucheva et al, 2004;Radivojac et al, 2010).…”