Multichain Immune Recognition Receptor Signaling: From Spatiotemporal Organization to Human Disease (Advances in Experimental Medicine and Biology (640))

ALEXANDER SIGALOV, PhD, is a Research Assistant Professor in the Department of Pathology at the University of Massachusetts Medical School in Worcester, Massachusetts, USA. His main research interests include protein intrinsic disorder and oligomericity in the context of transmembrane signal transduction, the molecular mechanisms underlying immune receptor-mediated signaling and ways to control these processes and thus to modulate the immune response, as well as the development and applications of novel targets and strategies for innovative immune therapy. He discovered and investigated a very unusual and unique biophysical phenomenon, the homooligomerization of intrinsically disordered proteins, thus providing the first evidence for the existence of specific interactions between unfolded protein molecules. In the field of immunology, he unraveled a long-standing mystery of transmembrane signaling and immune cell activation triggered by multichain immune recognition receptors. Later, he developed a novel concept of platelet inhibition and invented a novel class of platelet inhibitors. In the field of immune therapy, he proposed new therapeutic strategies for a variety of malignancies and immune disorders, including immunodeficiencies, inflammatory and autoimmune diseases, allergy and HIV. He is a member of the American Association for the Advancement of Science and the Biophysical Society, USA. Alexander Sigalov received his academic degrees (MSc in Chemistry and a PhD in Organic Chemistry) from Moscow State University, Russia.

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. These Receptors Share Common Structural Features Including Extracellular Ligand-binding Domains And Intracellular Signaling Domains Intriguingly Carried On Separate Subunits. Another Important Feature That Links Members Of The Mirrfamily Is The Presence Of One Or More Copies Of A Cytoplasmic Structural Module Termed The Immunoreceptor Tyrosine-based Activation Motif (itam). Itams Consist Of Conserved Sequences Of Amino Acids That Contain Two Appropriately Spaced Tyrosines (yxxl/ix6-8yxxl/i, Where X Denotes Non-conserved Residues). Following Receptor Engagement, Phosphorylation Of Itam Tyrosine Residues Represents One Of The Earliest Events In The Signaling Cascade. Although The Mirr-mediated Ligand Recognition And The Mirr-triggered Downstream Signaling Cascades Are Believed To Be Among The Best Studied In Biology In Recent Years, At Present The Spatial Organization Of The Mirrs, Its Reorganization In Response To Ligand Binding As Well As The Molecular Mechanisms Underlying The Initiation Of Mirrsignaling Remain To Be Elucidated.

mirr-mediated Signal Transduction Plays An Important Role In Both Health And Disease, Making These Receptors Attractive Targets For Rational Intervention In A Variety Of Immune Disorders. Thus, Future Therapeutic Strategies Depend On Our Detailed Understanding Of The Molecular Mechanisms Underlying Mirrtriggering And Subsequent Transmembrane Signal Transduction. In Addition, Knowing These Mechanisms Would Provide A New Handle In Dissecting The Basic Structural And Functional Aspects Of The Immune Response.

the Central Idea Of This Book Is To Show That The Structural Similarity Of The Mirrs Determines The General Principles Underlying Mirr-mediated Transmembrane Signaling Mechanisms And Also Provides The Basis For Existing And Future Therapeutic Strategies Targeting Mirrs. The Reviews Assembled In This Book Detail The Progress In Defining And Controlling The Spatiotemporal Organization Of Key Events In Immune Cell Activation. An Improved Understanding Of Mirr-mediated Signaling Has Numerous Potential Practical Applications, From The Rational Design Of Drugs And Vaccines To The Engineering Of Cells For Biotechnological Purposes. Section I Reviews The Spatial Organization And Physiological Function Of Mirrfamily Members Such As Tcell Receptor, B Cell Receptor, Fc Receptors, Natural Killer Cell Receptors And The Platelet Collagen Receptor Glycoprotein Vi. Section Ii Focuses On Current Models Of Mirrtriggering And Highlights Modern Technologies Available To Visualize Cell-cell Interaction Contacts Such As Immunological Synapse And Also To Measure Protein-protein Interactions In Space In Real Time. Potential Therapeutic Strategies Targeting Mirr-mediated Signaling Are Briefly Reviewed In Section Iii.

this Book Summarizes Current Knowledge In This Field And Illustrates How Control Of Mirr-triggered Signaling Could Become A Potential Target For Medical Intervention, Thus Bridging Basic And Clinical Immunology. Describing The Molecular Basis Of Mirr-mediated Transmembrane Signaling, This Volume Addresses A Broad Audience Ranging From Biochemists And Molecular And Structural Biologists To Basic And Clinical Immunologists And Pharmacologists.

T-cell receptor / Jose M. Rojo, Raquel Bello. and Pilar Portoløs B-cell receptor / Randall J. Brezski and John G. Monroe FC receptors / Maree S. Powell and P. Mark Hogarth Natural killer cell receptors / Roberto Biassoni Platelet glycoprotein vi / Stephanie M. Jung and Masaaki Moroi Clustering models / Wolfgang W.A. Schamel and Michael Reth Segregation models / Elaine P. Dopfer ... [et al.] Kinetic proofreading model / Byron Goldstein ... [et al.] Serial triggering model / Jacob Rachmilewitz Conformational model / Ruth M. Risueøo, Angel R. Ortiz, and Balbino Alarcøn Permissive geometry model / Susana Minguet and Wolfgang W.A. Schamel Signaling chain homooligomerization (SCHOOL) model / Alexander B. Sigalov Visualization of cell-cell interactioncontacts : synapses and kinapses / Michael L. Dustin Visualization of protein interactions in living cells / Tomasz Zal Immunogenicity in peptide immunotherapy : from self/nonself to similar/dissimilar sequences / Darja Kanduc Therapeutic application of transmembrane T and natural killer cell receptor peptides / Nicholas Manolios ... [et al.] FC receptor targeting in the treatment of allergy, autoimmune diseases, and cancer / Akira Nakamura, Tomohiro Kubo, and Toshiyuki Takai Therapeutic blockade of T-cell antigen receptor signal transduction and costimulation in autoimmune disease / Joseph R. Podojil, Danielle M. Turley, and Stephen D. Miller MHC and MHC-like molecules structural perspectives on the design of molecular vaccines / Vasso Apostolopoulos, Eliada Lazoura, and Minmin Yu SCHOOL model and new targeting strategies / Alexander B. Sigalov Immune receptor signaling, aging, and autoimmunity / Anis Larbi, Tamas Føløp, and Graham Pawelec Viral pathogenesis, modulation of immune receptor signaling, and treatment / Walter M. Kim and Alexander B. Sigalov. Front Matter....Pages i-xxvii T-Cell Receptor....Pages 1-11 B-Cell Receptor....Pages 12-21 Fc Receptors....Pages 22-34 Natural Killer Cell Receptors....Pages 35-52 Platelet Glycoprotein VI....Pages 53-63 Clustering Models....Pages 64-73 Segregation Models....Pages 74-81 Kinetic Proofreading Model....Pages 82-94 Serial Triggering Model....Pages 95-102 Conformational Model....Pages 103-112 Permissive Geometry Model....Pages 113-120 Signaling Chain Homooligomerization (SCHOOL) Model....Pages 121-163 Visualization of Cell-Cell Interaction Contacts-Synapses and Kinapses....Pages 164-182 Visualization of Protein Interactions in Living Cells....Pages 183-197 Immunogenicity in Peptide-Immunotherapy: From Self/Nonself to Similar/Dissimilar Sequences....Pages 198-207 Therapeutic Application of Transmembrane T and Natural Killer Cell Receptor Peptides....Pages 208-219 Fc Receptor Targeting in the Treatment of Allergy, Autoimmune Diseases and Cancer....Pages 220-233 Therapeutic Blockade of T- Cell Antigen Receptor Signal Transduction and Costimulation in Autoimmune Disease....Pages 234-251 MHC and MHC-Like Molecules: Structural Perspectives on the Design of Molecular Vaccines....Pages 252-267 SCHOOL Model and New Targeting Strategies....Pages 268-311 Immune Receptor Signaling, Aging and Autoimmunity....Pages 312-324 Viral Pathogenesis, Modulation of Immune Receptor Signaling and Treatment....Pages 325-349 Back Matter....Pages 351-357 The central idea of this book is to show that the structural similarity of the MIRRs determines the general principles underlying MIRR-mediated transmembrane signaling mechanisms and furthermore, provides the basis for existing and future therapeutic strategies targeting MIRRs. This book intends to assemble reviews on the progress in defining and controlling the spatiotemporal organization of key events in immune cell activation. Improved understanding of MIRR-mediated signaling has a number of potential practical applications, from the rational design of drugs and vaccines to the engineering of cells for biotechnological purposes. In Section 1, spatial organization and physiological function of the MIRR family members such as T cell receptor (TCR), B cell receptor (BCR), Fc receptors, natural killer (NK) cell receptors, and platelet glycoprotein VI (GPVI) will be reviewed. Section 2 will focus on current models of MIRR-triggering and highlight modern technologies to visualiz. Shows that the structural similarity of the Multichain Immune Recognition Receptors (MIRRs) determines the general principles underlying MIRR-mediated transmembrane signaling mechanisms. This book provides the basis for existing and future therapeutic strategies targeting MIRRs This book shows how the structural similarity of MIRRs determines the general principles underlying MIRR-mediated transmembrane signaling mechanisms. In so doing, it provides the basis for existing and future therapeutic strategies targeting MIRRs.