Structural immunology of complement receptors 3 and 4

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Structural immunology of complement receptors 3 and 4. / Vorup-Jensen, Thomas; Jensen, Rasmus Kjeldsen.

I: Frontiers in Immunology, Bind 9, Nr. NOV, 2716, 26.11.2018, s. 1-20.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisReviewForskningpeer review

Harvard

Vorup-Jensen, T & Jensen, RK 2018, 'Structural immunology of complement receptors 3 and 4', Frontiers in Immunology, bind 9, nr. NOV, 2716, s. 1-20. https://doi.org/10.3389/fimmu.2018.02716

APA

Vorup-Jensen, T., & Jensen, R. K. (2018). Structural immunology of complement receptors 3 and 4. Frontiers in Immunology, 9(NOV), 1-20. [2716]. https://doi.org/10.3389/fimmu.2018.02716

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Vorup-Jensen, Thomas ; Jensen, Rasmus Kjeldsen. / Structural immunology of complement receptors 3 and 4. I: Frontiers in Immunology. 2018 ; Bind 9, Nr. NOV. s. 1-20.

Bibtex

@article{05126524ae2244628c3b695aad85d553,
title = "Structural immunology of complement receptors 3 and 4",
abstract = "Complement receptors (CR) 3 and 4 belong to the family of beta-2 (CD18) integrins. CR3 and CR4 are often co-expressed in the myeloid subsets of leukocytes, but they are also found in NK cells and activated T and B lymphocytes. The heterodimeric ectodomain undergoes considerable conformational change in order to switch the receptor from a structurally bent, ligand-binding in-active state into an extended, ligand-binding active state. CR3 binds the C3d fragment of C3 in a way permitting CR2 also to bind concomitantly. This enables a hand-over of complement-opsonized antigens from the cell surface of CR3-expressing macrophages to the CR2-expressing B lymphocytes, in consequence acting as an antigen presentation mechanism. As a more enigmatic part of their functions, both CR3 and CR4 bind several structurally unrelated proteins, engineered peptides, and glycosaminoglycans. No consensus motif in the proteinaceous ligands has been established. Yet, the experimental evidence clearly suggest that the ligands are primarily, if not entirely, recognized by a single site within the receptors, namely the metal-ion dependent adhesion site (MIDAS). Comparison of some recent identified ligands points to CR3 as inclined to bind positively charged species, while CR4, by contrast, binds strongly negative-charged species, in both cases with the critical involvement of deprotonated, acidic groups as ligands for the Mg2+ ion in the MIDAS. These properties place CR3 and CR4 firmly within the realm of modern molecular medicine in several ways. The expression of CR3 and CR4 in NK cells was recently demonstrated to enable complement-dependent cell cytotoxicity toward antibody-coated cancer cells as part of biological therapy, constituting a significant part of the efficacy of such treatment. With the flexible principles of ligand recognition, it is also possible to propose a response of CR3 and CR4 to existing medicines thereby opening a possibility of drug repurposing to influence the function of these receptors. Here, from advances in the structural and cellular immunology of CR3 and CR4, we review insights on their biochemistry and functions in the immune system.",
keywords = "cell adhesion, complement, complement receptors, divalent metal ions, drug repurposing, innate immunity, integrins, von willebrand facor A (VWA) domain",
author = "Thomas Vorup-Jensen and Jensen, {Rasmus Kjeldsen}",
year = "2018",
month = "11",
day = "26",
doi = "10.3389/fimmu.2018.02716",
language = "English",
volume = "9",
pages = "1--20",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Research Foundation",
number = "NOV",

}

RIS

TY - JOUR

T1 - Structural immunology of complement receptors 3 and 4

AU - Vorup-Jensen, Thomas

AU - Jensen, Rasmus Kjeldsen

PY - 2018/11/26

Y1 - 2018/11/26

N2 - Complement receptors (CR) 3 and 4 belong to the family of beta-2 (CD18) integrins. CR3 and CR4 are often co-expressed in the myeloid subsets of leukocytes, but they are also found in NK cells and activated T and B lymphocytes. The heterodimeric ectodomain undergoes considerable conformational change in order to switch the receptor from a structurally bent, ligand-binding in-active state into an extended, ligand-binding active state. CR3 binds the C3d fragment of C3 in a way permitting CR2 also to bind concomitantly. This enables a hand-over of complement-opsonized antigens from the cell surface of CR3-expressing macrophages to the CR2-expressing B lymphocytes, in consequence acting as an antigen presentation mechanism. As a more enigmatic part of their functions, both CR3 and CR4 bind several structurally unrelated proteins, engineered peptides, and glycosaminoglycans. No consensus motif in the proteinaceous ligands has been established. Yet, the experimental evidence clearly suggest that the ligands are primarily, if not entirely, recognized by a single site within the receptors, namely the metal-ion dependent adhesion site (MIDAS). Comparison of some recent identified ligands points to CR3 as inclined to bind positively charged species, while CR4, by contrast, binds strongly negative-charged species, in both cases with the critical involvement of deprotonated, acidic groups as ligands for the Mg2+ ion in the MIDAS. These properties place CR3 and CR4 firmly within the realm of modern molecular medicine in several ways. The expression of CR3 and CR4 in NK cells was recently demonstrated to enable complement-dependent cell cytotoxicity toward antibody-coated cancer cells as part of biological therapy, constituting a significant part of the efficacy of such treatment. With the flexible principles of ligand recognition, it is also possible to propose a response of CR3 and CR4 to existing medicines thereby opening a possibility of drug repurposing to influence the function of these receptors. Here, from advances in the structural and cellular immunology of CR3 and CR4, we review insights on their biochemistry and functions in the immune system.

AB - Complement receptors (CR) 3 and 4 belong to the family of beta-2 (CD18) integrins. CR3 and CR4 are often co-expressed in the myeloid subsets of leukocytes, but they are also found in NK cells and activated T and B lymphocytes. The heterodimeric ectodomain undergoes considerable conformational change in order to switch the receptor from a structurally bent, ligand-binding in-active state into an extended, ligand-binding active state. CR3 binds the C3d fragment of C3 in a way permitting CR2 also to bind concomitantly. This enables a hand-over of complement-opsonized antigens from the cell surface of CR3-expressing macrophages to the CR2-expressing B lymphocytes, in consequence acting as an antigen presentation mechanism. As a more enigmatic part of their functions, both CR3 and CR4 bind several structurally unrelated proteins, engineered peptides, and glycosaminoglycans. No consensus motif in the proteinaceous ligands has been established. Yet, the experimental evidence clearly suggest that the ligands are primarily, if not entirely, recognized by a single site within the receptors, namely the metal-ion dependent adhesion site (MIDAS). Comparison of some recent identified ligands points to CR3 as inclined to bind positively charged species, while CR4, by contrast, binds strongly negative-charged species, in both cases with the critical involvement of deprotonated, acidic groups as ligands for the Mg2+ ion in the MIDAS. These properties place CR3 and CR4 firmly within the realm of modern molecular medicine in several ways. The expression of CR3 and CR4 in NK cells was recently demonstrated to enable complement-dependent cell cytotoxicity toward antibody-coated cancer cells as part of biological therapy, constituting a significant part of the efficacy of such treatment. With the flexible principles of ligand recognition, it is also possible to propose a response of CR3 and CR4 to existing medicines thereby opening a possibility of drug repurposing to influence the function of these receptors. Here, from advances in the structural and cellular immunology of CR3 and CR4, we review insights on their biochemistry and functions in the immune system.

KW - cell adhesion

KW - complement

KW - complement receptors

KW - divalent metal ions

KW - drug repurposing

KW - innate immunity

KW - integrins

KW - von willebrand facor A (VWA) domain

UR - http://www.scopus.com/inward/record.url?scp=85057387646&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2018.02716

DO - 10.3389/fimmu.2018.02716

M3 - Review

C2 - 30534123

AN - SCOPUS:85057387646

VL - 9

SP - 1

EP - 20

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - NOV

M1 - 2716

ER -