Multichain Immune Recognition Receptor Signaling

Volume 640 of the series Advances in Experimental Medicine and Biology pp 121-163

Signaling Chain Homooligomerization (SCHOOL) Model

  • Alexander B. SigalovAffiliated withDepartment of Pathology, University of Massachusetts Medical School

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Multichain immune recognition receptors (MIRRs) represent a family of surface receptors 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 of MIRR 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 of MIRR-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 of transmembrane 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.