GTPasebinding

GTPase-binding refers to the interaction between small GTPases of the Ras superfamily and other proteins that recognize the active, GTP-bound conformation of these switches. The term encompasses both effector proteins and modular domains within signaling proteins that specifically bind GTPases in their active state, thereby propagating cellular signals that regulate growth, differentiation, cytoskeleton organization, vesicle trafficking, and gene expression.

Small GTPases act as molecular switches with intrinsic GTPase activity. When bound to GTP, they undergo conformational changes in their switch I and switch II regions, creating surfaces that are recognized by downstream effectors. GTPase binding is generally less favorable to GDP-bound forms, providing a mechanism for directional signaling. Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) regulate this state, while GTPase-binding proteins interpret it.

Notable GTPase-binding domains include the Ras-binding domain (RBD), found in effectors such as Raf kinases and PI3K; the CRIB motif, which binds Cdc42 and Rac GTPases and is present in effectors like PAK; and the p21-binding domain (PBD) in PAK family and related kinases. Some GTPases interact via other interfaces in Rabs and Arfs that mediate vesicle trafficking. The binding can be isoform-specific; for example, Ras preferentially engages Raf-family RBDs, while Cdc42 and Rac engage CRIB-containing proteins. Structural affinity is influenced by post-translational modifications and subcellular localization.

GTPase-binding underlies key signaling pathways such as the MAPK cascade, actin cytoskeleton remodeling, and membrane trafficking. Aberrations in GTPase-binding interactions, through mutations in GTPases or effectors or mislocalization, are implicated in cancers and neurological disorders. Research on GTPase-binding helps map signaling networks and identify potential therapeutic targets.