GRAF1

GRAF1 is a BAR-domain containing Rho GTPase-activating protein involved in coordinating membrane remodeling with cytoskeletal dynamics. As a member of the GRAF family, it participates in regulation of actin and membrane trafficking in various cell types. GRAF1 functions by stimulating the GTPase activity of Rho family proteins, particularly Cdc42 and Rac1, thereby modulating pathways that control actin polymerization and membrane curvature.

Structure: The protein features an N-terminal BAR domain that contributes to sensing and generating membrane curvature, followed by a central RhoGAP domain that accelerates GTP hydrolysis on Rho GTPases. A C-terminal region contains lipid-binding motifs and interaction platforms, including PH and SH3 domains, which mediate membrane association and protein interactions.

Cellular roles: GRAF1 localizes to the plasma membrane and intracellular membranes. It participates in clathrin-independent endocytosis and other membrane trafficking routes, coordinating vesicle formation with actin remodeling and adhesion signaling. By linking membrane curvature to Rho GTPase activity, GRAF1 helps regulate cell shape, migration, and adhesion dynamics, and it can be recruited to focal adhesions via interactions with adapter proteins.

Regulation and interactions: GRAF1 activity is influenced by phosphoinositide binding through its PH domain and by protein–protein interactions with components of focal adhesions and endocytic machinery. Post-translational modifications may modulate GAP activity and localization.

Clinical significance: Aberrant expression or mutations in GRAF1 or related GRAF family members have been studied in relation to cancer cell migration and invasion, as well as other disorders involving cytoskeletal dynamics and endocytosis. GRAF1 is studied alongside GRAF2 and GRAF3 as part of the same regulatory network.