General structural features that regulate integrin affinity revealed by atypical αVβ8

Wang, Jianchuan; Su, Yang; Iacob, Roxana E.; Engen, John R.; Springer, Timothy A.

doi:10.1038/s41467-019-13248-5

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

Journal Article · 02 December 2019 · Nature Communications

DOI: https://doi.org/10.1038/s41467-019-13248-5 · OSTI ID:1600834

^[1]; Su, Yang ^[1]; Iacob, Roxana E. ^[2];

^[2];

^[1]

Boston Children's Hospital, MA (United States); Harvard Medical School, Boston, MA (United States)
Northeastern Univ., Boston, MA (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); Waters Corporation

OSTI ID:: 1600834

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 10; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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