General structural features that regulate integrin affinity revealed by atypical ?V?8.

ABSTRACT: Integrin ?V?8, which like ?V?6 functions to activate TGF-?s, is atypical. Its ?8 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 ?V?8 and ?V?6. Lack of a binding site for one of three ?I domain divalent cations and a unique ?6-?7 loop conformation in ?8 facilitate movements of the ?1 and ?1' helices at the ligand binding pocket toward the high affinity state, without coupling to ?6-?7 loop reshaping and ?7-helix pistoning that drive large changes in ?I domain-hybrid domain orientation seen in other integrins. Reciprocal swaps between ?6 and ?8 ?I domains increase affinity of ?V?6 and decrease affinity of ?V?8 and define features that regulate affinity of the ?I domain and its coupling to the hybrid domain.

SUBMITTER: Wang J 

PROVIDER: S-EPMC6889490 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature