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Title: General structural features that regulate integrin affinity revealed by atypical αVβ8

Abstract

Integrin αVβ8, which like αVβ6 functions to activate TGF-βs, is atypical. Its β8 subunit binds to a distinctive cytoskeleton adaptor and does not exhibit large changes in conformation upon binding to ligand. Here, crystal structures, hydrogen-deuterium exchange dynamics, and affinity measurements on mutants are used to compare αVβ8 and αVβ6. Lack of a binding site for one of three βI domain divalent cations and a unique β6-α7 loop conformation in β8 facilitate movements of the α1 and α1’ helices at the ligand binding pocket toward the high affinity state, without coupling to β6-α7 loop reshaping and α7-helix pistoning that drive large changes in βI domain-hybrid domain orientation seen in other integrins. Reciprocal swaps between β6 and β8 βI domains increase affinity of αVβ6 and decrease affinity of αVβ8 and define features that regulate affinity of the βI domain and its coupling to the hybrid domain.

Authors:
ORCiD logo [1];  [1];  [2]; ORCiD logo [2]; ORCiD logo [1]
  1. Boston Children's Hospital, MA (United States); Harvard Medical School, Boston, MA (United States)
  2. Northeastern Univ., Boston, MA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); Waters Corporation
OSTI Identifier:
1600834
Grant/Contract Number:  
HL-134723
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Cell signalling; Integrins; Mass spectrometry; X-ray crystallography

Citation Formats

Wang, Jianchuan, Su, Yang, Iacob, Roxana E., Engen, John R., and Springer, Timothy A. General structural features that regulate integrin affinity revealed by atypical αVβ8. United States: N. p., 2019. Web. https://doi.org/10.1038/s41467-019-13248-5.
Wang, Jianchuan, Su, Yang, Iacob, Roxana E., Engen, John R., & Springer, Timothy A. General structural features that regulate integrin affinity revealed by atypical αVβ8. United States. https://doi.org/10.1038/s41467-019-13248-5
Wang, Jianchuan, Su, Yang, Iacob, Roxana E., Engen, John R., and Springer, Timothy A. Mon . "General structural features that regulate integrin affinity revealed by atypical αVβ8". United States. https://doi.org/10.1038/s41467-019-13248-5. https://www.osti.gov/servlets/purl/1600834.
@article{osti_1600834,
title = {General structural features that regulate integrin affinity revealed by atypical αVβ8},
author = {Wang, Jianchuan and Su, Yang and Iacob, Roxana E. and Engen, John R. and Springer, Timothy A.},
abstractNote = {Integrin αVβ8, which like αVβ6 functions to activate TGF-βs, is atypical. Its β8 subunit binds to a distinctive cytoskeleton adaptor and does not exhibit large changes in conformation upon binding to ligand. Here, crystal structures, hydrogen-deuterium exchange dynamics, and affinity measurements on mutants are used to compare αVβ8 and αVβ6. Lack of a binding site for one of three βI domain divalent cations and a unique β6-α7 loop conformation in β8 facilitate movements of the α1 and α1’ helices at the ligand binding pocket toward the high affinity state, without coupling to β6-α7 loop reshaping and α7-helix pistoning that drive large changes in βI domain-hybrid domain orientation seen in other integrins. Reciprocal swaps between β6 and β8 βI domains increase affinity of αVβ6 and decrease affinity of αVβ8 and define features that regulate affinity of the βI domain and its coupling to the hybrid domain.},
doi = {10.1038/s41467-019-13248-5},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {12}
}

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