Allosteric modulation of NF1 GAP: Differential distributions of catalytically competent populations in loss-of-function and gain-of-function mutants.

ABSTRACT: Neurofibromin (NF1), a Ras GTPase-activating protein (GAP), catalyzes Ras-mediated GTP hydrolysis and thereby negatively regulates the Ras/MAPK pathway. NF1 mutations can cause neurofibromatosis type 1 manifesting tumors, and neurodevelopmental disorders. Exactly how the missense mutations in the GAP-related domain of NF1 (NF1^GRD) allosterically impact NF1 GAP to promote these distinct pathologies is unclear. Especially tantalizing is the question of how same-domain, same-residue NF1^GRD variants exhibit distinct clinical phenotypes. Guided by clinical data, we take up this dilemma. We sampled the conformational ensembles of NF1^GRD in complex with GTP-bound K-Ras4B by performing molecular dynamics simulations. Our results show that mutations in NF1^GRD</

SUBMITTER: Xu L 

PROVIDER: S-EPMC11751910 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature