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General structural features that regulate integrin affinity revealed by atypical αVβ8

ABSTRACT: Integrins αVβ8 and αVβ6 are master activators of proTGF-βs. Whereas most integrins including αVβ6 are activated by tensile force applied by the cytoskeleton, αVβ8 links differently to the cytoskeleton and lacks the open headpiece conformation that represents the high affinity state of other integrins. Here, we shed light on the atypical activation mechanism of integrin αVβ8 using crystal structures in the absence and presence of proTGF-β1 peptide, comparisons of the hydrogen deuterium exchange dynamics of αVβ8 and αVβ6, and affinity measurements on mutants in which structurally atypical residues of αVβ8 and typical residues of αVβ6 were reciprocally exchanged.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: John R. Engen

LAB HEAD: John R. Engen

PROVIDER: PXD014348 | Pride | 2019-12-03

REPOSITORIES: Pride

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			Action	DRS
	091117_avb6_UN1.raw.zip	Raw
	091117_avb6_UN2.raw.zip	Raw
	091117_avb6_UN3.raw.zip	Raw
	091117_avb6_UN4.raw.zip	Raw
	091117_avb8_UN1.raw.zip	Raw

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Publications

General structural features that regulate integrin affinity revealed by atypical αVβ8.

Wang Jianchuan J Su Yang Y Iacob Roxana E RE Engen John R JR Springer Timothy A TA

Nature communications 20191202 1

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 ...[more]

PMID: 31792290

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