Unique transmembrane domain interactions differentially modulate integrin ?v?3 and ?IIb?3 function.

ABSTRACT: Lateral transmembrane (TM) helix-helix interactions between single-span membrane proteins play an important role in the assembly and signaling of many cell-surface receptors. Often, these helices contain two highly conserved yet distinct interaction motifs, arranged such that the motifs cannot be engaged simultaneously. However, there is sparse experimental evidence that dual-engagement mechanisms play a role in biological signaling. Here, we investigate the function of the two conserved interaction motifs in the TM domain of the integrin ?3-subunit. The first motif uses reciprocating "large-large-small" amino acid packing to mediate the interaction of the ?3 and ?IIb TM domains and maintain the inactive resting conformation of the platelet integrin ?IIb?3. The second motif, S-x3-A-x3-I, is a variant of the classical "G-x3-G" motif. Using site-directed mutagenesis, optical trap-based force spectroscopy, and molecular modeling, we show that S-x3-A-x3-I does not engage ?IIb but rather mediates the interaction of the ?3 TM domain with the TM domain of the ?v-subunit of the integrin ?v?3. Like ?IIb?3, ?v?3 on circulating platelets is inactive, and in the absence of platelet stimulation is unable to interact with components of the subendothelial matrix. However, disrupting any residue in the ?3 S-x3-A-x3-I motif by site-directed mutations is sufficient to induce ?v?3 binding to the ?v?3 ligand osteopontin and to the monoclonal antibody WOW-1. Thus, the ?3-integrin TM domain is able to engage in two mutually exclusive interactions that produce alternate ?-subunit pairing, creating two integrins with distinct biological functions.

SUBMITTER: Litvinov RI 

PROVIDER: S-EPMC6589676 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature