Structural implications of mutations in the bI domain of integrin b3 on fibrinogen binding using molecular dynamics simulations

ABSTRACT: Integrin IIb3 is anchored to the platelet cell membrane in a bent and closed conformation. Divalent cations in the MIDAS, ADMIDAS, and SyMBS coordinate the ligand binding site. When ligand binds to the headpiece formed by the interacting IIb -propeller and 3 I domains, the latter undergoes displacement in the lower regions of the 3 subunit transitioning from a low-to-high affinity state and positioning the metal ions allosterically to increase the affinity for ligand binding followed by the outward swing-out of its hybrid domain. This study was aimed at unravelling the impact of some of the missense mutations in the I domain on fibrinogen binding. Accordingly, 90 missense mutations reported in the I, PSI, and hybrid domains were screened for their pathogenicity, stability, and evolutionary conservation. Among these, D113H, D119N, and M124V located near the metal ions involved in ligand binding were analyzed for their impact on the binding affinities of both IIb-3 and IIb3-fibrinogen complexes. The fibrinogen-bound structures were further studied using molecular dynamics simulations which revealed that the D113H mutation affected ligand binding due to the loss of a hydrogen bond thus preventing a direct contact with metal ions. The D119N mutation was structurally evaluated for its indirect interaction with fibrinogen via M124. The deleterious M124V mutation destabilized the structure by abrogating fibrinogen binding

ORGANISM(S): Homo sapiens (human)

SUBMITTER: FINOLA PRIYADHARSHINI C 

PROVIDER: S-BSST2146 | biostudies-other |

REPOSITORIES: biostudies-other