Signaling Chain Homooligomerization (SCHOOL) Model

Abstract

Multichain immune recognitionreceptors (MIRRs) represent a family of surfacereceptors expressed on different cells of the hematopoietic system and function to transduce signals leading to a variety of biologic responses. The most intriguing and distinct structural feature ofMIRR family members is that extracellular recognition domains and intracellular signaling domains are located on separate subunits. The biochemical cascades triggered by MIRRs are understood in significant detail, however, the mechanism by which extracellular ligand binding initiates intracellular signal transduction processes is not clear and no model fully explains how MIRR signaling commences. In this Chapter, I describe a novel mechanistic model of MIRR-mediated signal transduction, the signaling chain homooligomerization (SCHOOL) model. The basic concept of this model assumes that the structural similarity of the MIRRs provides the basis for the similarity in the mechanisms ofMIRR-mediated transmembrane signaling. Within the SCHOOL model, MIRR triggering is considered to be a result of the ligand-induced interplay between (1) intrareceptor transmembrane interactions between MIRR recognition and signaling subunits that stabilize and maintain receptor integrity and (2) interreceptor homointeractions between MIRR signaling subunits that lead to the formation of oligomeric signaling structures, thus triggering the receptors and initiating the signaling cascade. Thus, the SCHOOL model is based on specific protein-protein interactions--biochemical processes that can be influenced and controlled. In this context, this plausible and easily testable model is fundamentally different from those previously suggested for particular MIRRs and has several important advantages. The basic principles oftransmembrane signaling learned from the SCHOOL model may be used in different fields of immunology and cell biology to describe, explain and predict immunological phenomena and processes mediated by structurally related but functionally different membrane receptors. Important applications of the SCHOOL model in clinical immunology, molecular pharmacology and virology are described in the Chapters 20 and 22 of this book.

The SCHOOL of nature: II. Protein order, disorder, and oligomericity in transmembrane signaling

“…However, it does not necessarily mean that mode II (binding without folding) is also physiologically irrelevant. For example, within the SCHOOL model, 71,74 homointeractions between CYTO domains of the ITAM-containing receptor signaling subunits are suggested to be necessary and sufficient to trigger the receptor. Thus, membrane binding of ζ cyt , CD3ε cyt and FcεRγ cyt might prevent homo-oligomerization of these CYTO domains 9 in receptor clusters on the surface of resting cells and during random encounters of receptors diffusing in the cell membrane.…”

“…4). 2,52,71,74,77,78 Because many multichain activating receptors are immune receptors, they are all commonly referred to as multichain immune recognition receptors (MIRRs). 2,72,77 Assuming that the similar structural architecture of the receptors dictates similar mechanisms of receptor triggering and subsequent transmembrane signaling, one can suggest that the targets revealed by these mechanisms are similar in seemingly unrelated diseases.…”

Calbindin-D28K acts as a calcium-dependent chaperone suppressing α-synuclein fibrillation in vitro

“…This is an unusual but not unprecedented observation. The lack of considerable structural changes in complexes of natively unfolded proteins with their binding partners (either themselves or other proteins) was earlier observed for the caldesmon-calmodulin complex formation [51], dimerization and oligomerization of α-synuclein [52] and for the functional self-oligomerization of intrinsically disordered cytoplasmic domains of immune receptor signaling subunits [53][54][55].…”

Cells diversify transmembrane signaling through the controlled chaos of protein disorder

“…Most of experimental data in the literature reported to date strongly support the distinct rather than redundant functions for the ITAM signaling modules including those located on the different signaling chains 39,[44][45][46][47][48][49][50][51][52][53][54][55] and those located on the same signaling module (e.g., 3 different ITAMs on TCR ζ chain). 56 Within the SCHOOL model, 10,11,42,43 cytoplasmic homooligomerization controls the ITAM signaling through the different patterns of MIRR signaling subunit homooligomerization 11,43 that produce distinct activation signals provided by different ITAMs. This assumes the combinatorial nature of MIRR-mediated signaling and can provide a molecular explanation for the diversity of the immune response.…”

“…The answer to this question comes from a recently proposed novel model of transmembrane signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model. 2,3,[10][11]42 First introduced for MIRRs, 10,43 this model suggests that formation of competent signaling homooligomers in cytoplasmic milieu is the necessary and sufficient event to trigger MIRRs and induce cell activation. This dictates several important restraints on multivalent ligand binding-induced MIRR signaling: (1) sufficient interreceptor proximity in receptor dimers/oligomers, (2) correct (permissive for signaling) relative orientation of the receptors in the nature and principles of receptor signaling, but also about the way we perform fundamental research and design therapies of receptor-mediated diseases for the foreseeable future.…”