CDB25:0003283 CD40LG — ITGAV

Experimentally validated in Human; Orthology-inferred in Mouse, Rat, Frog, Zebrafish, Chicken, Macaque, Pig, Dog, Cow, Chimp, Horse, Marmoset, Sheep

Title

Journal:; Year Published:

Abstract

Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling.

Journal of immunology, 2019; PubMed, Homo sapiens CD40LG — Homo sapiens ITGAV
ABSTRACT: CD40L plays a major role in immune response and is a major therapeutic target for inflammation. Integrin α5β1 and CD40 simultaneously bind to CD40L. It is unclear if α5β1 and CD40 work together in CD40/CD40L signaling or how α5β1 binds to CD40L. In this article, we describe that the integrin-binding site of human CD40L is predicted to be located in the trimeric interface by docking simulation. Mutations in the predicted integrin-binding site markedly reduced the binding of α5β1 to CD40L. Several CD40L mutants defective in integrin binding were defective in NF-κB activation and B cell activation and suppressed CD40L signaling induced by wild-type CD40L; however, they still bound to CD40. These findings suggest that integrin α5β1 binds to monomeric CD40L through the binding site in the trimeric interface of CD40L, and this plays a critical role in CD40/CD40L signaling. Integrin αvβ3, a widely distributed vascular integrin, bound to CD40L in a KGD-independent manner, suggesting that αvβ3 is a new CD40L receptor. Several missense mutations in CD40L that induce immunodeficiency with hyper-IgM syndrome type 1 (HIGM1) are clustered in the integrin-binding site of the trimeric interface. These HIGM1 CD40L mutants were defective in binding to α5β1 and αvβ3 (but not to CD40), suggesting that the defect in integrin binding may be a causal factor of HIGM1. These findings suggest that α5β1 and αvβ3 bind to the overlapping binding site in the trimeric interface of monomeric CD40L and generate integrin-CD40L-CD40 ternary complex. CD40L mutants defective in integrins have potential as antagonists of CD40/CD40L signaling.

Soluble CD40L activates soluble and cell-surface integrin αvβ3, α5β1, and α4β1 by binding to the allosteric ligand-binding site (site 2).

The Journal of biological chemistry, 2021; PubMed, Homo sapiens CD40LG — Homo sapiens ITGAV
ABSTRACT: CD40L is a member of the TNF superfamily that participates in immune cell activation. It binds to and signals through several integrins, including αvβ3 and α5β1, which bind to the trimeric interface of CD40L. We previously showed that several integrin ligands can bind to the allosteric site (site 2), which is distinct from the classical ligand-binding site (site 1), raising the question of if CD40L activates integrins. In our explorations of this question, we determined that integrin α4β1, which is prevalently expressed on the same CD4+ T cells as CD40L, is another receptor for CD40L. Soluble (s)CD40L activated soluble integrins αvβ3, α5β1, and α4β1 in cell-free conditions, indicating that this activation does not require inside-out signaling. Moreover, sCD40L activated cell-surface integrins in CHO cells that do not express CD40. To learn more about the mechanism of binding, we determined that sCD40L bound to a cyclic peptide from site 2. Docking simulations predicted that the residues of CD40L that bind to site 2 are located outside of the CD40L trimer interface, at a site where four HIGM1 (hyper-IgM syndrome type 1) mutations are clustered. We tested the effect of these mutations, finding that the K143T and G144E mutants were the most defective in integrin activation, providing support that this region interacts with site 2. We propose that allosteric integrin activation by CD40L also plays a role in CD40L signaling, and defective site 2 binding may be related to the impaired CD40L signaling functions of these HIGM1 mutants.
Basic Information on CD40LG
Ligand Name: CD40 ligand
Other Symbols: HIGM1, IMD3, TNFSF5, CD40L, TRAP, gp39, hCD40L, CD154, CD40-L, HIGM1, T-BAM
Ligand Location: secreted based on hpa, perplexity, uniprot, cell membrane based on hpa, perplexity, uniprot
HGNC Gene Symbol Report: CD40LG
GeneCards: CD40LG
Functional Annotations for CD40LG
Gene Ontologies: PAN-GO, AmiGO 2
Expression Profile: Human Protein Atlas (RNA and protein), Human Cell Atlas (RNA), GEPIA cancer vs normal (RNA), GeneCards (RNA and protein)
Disease Annotations: MalaCards, OMIM, Open Targets Platform, DISEASES (text mining), AI summary (LLM)
Interactions with other Receptors for CD40LG
CD40LG — CD40 ・ CD40LG — ITGAM ・ CD40LG — ITGB2 ・ CD40LG — ITGA2B ・ CD40LG — ITGA4 ・ CD40LG — ITGA5 ・ CD40LG — ITGB1 ・ CD40LG — ITGB3
Basic Information on ITGAV
Receptor Name: integrin subunit alpha V
Other Symbols: VNRA, MSK8, VTNR, CD51
Receptor Location: cell membrane based on perplexity, uniprot
HGNC Gene Symbol Report: ITGAV
GeneCards: ITGAV
HGNC Gene Group: CD molecules, Integrins
Functional Annotations for ITGAV
Gene Ontologies: PAN-GO, AmiGO 2
Expression Profile: Human Protein Atlas (RNA and protein), Human Cell Atlas (RNA), GEPIA cancer vs normal (RNA), GeneCards (RNA and protein)
Disease Annotations: MalaCards, OMIM, Open Targets Platform, DISEASES (text mining), AI summary (LLM)
Interactions with other Ligands for ITGAV
ADAM15 — ITGAV ・ ADAM9 — ITGAV ・ ANGPTL3 — ITGAV ・ AZGP1 — ITGAV ・ COL1A1 — ITGAV ・ COL4A3 — ITGAV ・ CCN1 — ITGAV ・ EDIL3 — ITGAV ・ FBN1 — ITGAV ・ FGA — ITGAV ・ FGB — ITGAV ・ FGG — ITGAV ・ FN1 — ITGAV ・ IBSP — ITGAV ・ ICAM4 — ITGAV ・ L1CAM — ITGAV ・ LAMA4 — ITGAV ・ MFGE8 — ITGAV ・ NID1 — ITGAV ・ SPP1 — ITGAV ・ TGFB1 — ITGAV ・ TNC — ITGAV ・ VTN — ITGAV ・ CX3CL1 — ITGAV ・ CXCL12 — ITGAV ・ FNDC5 — ITGAV ・ PLA2G2A — ITGAV ・ ADAM23 — ITGAV ・ AGRN — ITGAV ・ ANGPT2 — ITGAV ・ CCN3 — ITGAV ・ COL18A1 — ITGAV ・ COMP — ITGAV ・ DMP1 — ITGAV ・ EGFL7 — ITGAV ・ FBLN2 — ITGAV ・ FCER2 — ITGAV ・ FGF1 — ITGAV ・ FGF2 — ITGAV ・ HMGB1 — ITGAV ・ IGF1 — ITGAV ・ IGF2 — ITGAV ・ IL1B — ITGAV ・ NRG1 — ITGAV ・ PECAM1 — ITGAV ・ PLAUR — ITGAV ・ POSTN — ITGAV ・ PTN — ITGAV ・ TGFB3 — ITGAV ・ THBS1 — ITGAV ・ THY1 — ITGAV ・ VWF — ITGAV
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