التفاصيل البيبلوغرافية
| العنوان: |
The V2 domain of HIV gp120 mimics an interaction between CD4 and integrin ⍺4β7. |
| المؤلفون: |
Van Ryk, Donald, Vimonpatranon, Sinmanus, Hiatt, Joe, Ganesan, Sundar, Chen, Nathalie, McMurry, Jordan, Garba, Saadiq, Min, Susie, Goes, Livia R., Girard, Alexandre, Yolitz, Jason, Licavoli, Isabella, Wei, Danlan, Huang, Dawei, Soares, Marcelo A., Martinelli, Elena, Cicala, Claudia, Arthos, James |
| المصدر: |
PLoS Pathogens; 12/8/2023, Vol. 19 Issue 12, p1-26, 26p |
| مصطلحات موضوعية: |
VIRAL tropism, CD4 antigen, INTEGRINS, HIV-1 glycoprotein 120, HIV, BINDING sites, T cells |
| مستخلص: |
The CD4 receptor, by stabilizing TCR-MHC II interactions, plays a central role in adaptive immunity. It also serves as the HIV docking receptor. The HIV gp120 envelope protein binds directly to CD4. This interaction is a prerequisite for viral entry. gp120 also binds to ⍺4β7, an integrin that is expressed on a subset of memory CD4+ T cells. HIV tropisms for CD4+ T cells and gut tissues are central features of HIV pathogenesis. We report that CD4 binds directly to ⍺4β7 in a dynamic way, consistent with a cis regulatory interaction. The molecular details of this interaction are related to the way in which gp120 interacts with both receptors. Like MAdCAM-1 and VCAM-1, two recognized ligands of ⍺4β7, the binding interface on CD4 includes 2 sites (1° and accessory), distributed across its two N-terminal IgSF domains (D1 and D2). The 1° site includes a sequence in the G β-strand of CD4 D2, KIDIV, that binds directly to ⍺4β7. This pentapeptide sequence occurs infrequently in eukaryotic proteins. However, a closely related and conserved sequence, KLDIV, appears in the V2 domain of gp120. KLDIV mediates gp120-⍺4β7 binding. The accessory ⍺4β7 binding site on CD4 includes Phe43. The Phe43 aromatic ring protrudes outward from one edge of a loop connecting the C'C" strands of CD4 D1. Phe43 is a principal contact for HIV gp120. It interacts with conserved residues in the recessed CD4 binding pocket. Substitution of Phe43 abrogates CD4 binding to both gp120 and ⍺4β7. As such, the interactions of gp120 with both CD4 and ⍺4β7 reflect elements of their interactions with each other. These findings indicate that gp120 specificities for CD4 and ⍺4β7 are interrelated and suggest that selective pressures which produced a CD4 tropic virus that replicates in gut tissues are linked to a dynamic interaction between these two receptors. Author summary: Integrins modulate cell trafficking and provide costimulatory signals to leukocytes. An increasing number have also been shown to interact in cis with immune receptors. Formation of these multi-receptor complexes is dynamic and typically serves a regulatory function. We report a cis interaction between ⍺4β7, the gut-homing integrin and CD4, a receptor that plays a central role in the adaptive immune response. CD4-⍺4β7 interactions share features with MAdCAM-1 and VCAM-1, two natural ligands that engage ⍺4β7 in trans. All three receptors engage ⍺4β7 through two discreet sites distributed across their two N-terminal IgSF domains. Specific features of the two ⍺4β7 binding sites on CD4 are related to HIV pathogenesis in a unique and informative way. HIV gp120 binds to both CD4 and ⍺4β7. A key finding of this report is that specific elements of gp120-CD4 and gp120-⍺4β7 interactions reflect the interaction of these two receptors with each other. We conclude that the selective pressures that resulted in a virus which infects and depletes gut CD4+ T cells are linked to CD4-⍺4β7 cis interactions. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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