Cell division control protein 42 homolog (Cdc42) – Intersectin-1 (ITSN1) binding interface (Cdc42-ITSN1 interface)

The Cell division control protein 42 homolog (Cdc42) – Intersectin-1 (ITSN1) binding interface is a pivotal regulatory junction in the Rho GTPase signaling pathway. Cdc42 acts as a molecular switch, alternating between an inactive GDP-bound form and an active GTP-bound form to regulate the actin cytoskeleton, cell polarity, and membrane trafficking (UniProt P60953). Intersectin-1 (ITSN1) serves as a Guanine Nucleotide Exchange Factor (GEF) that catalyzes this activation by interacting with the Switch I and Switch II regions of Cdc42 via its Dbl homology (DH) domain (Friesland et al., 2013). This specific interface is a therapeutic target because its hyperactivation is associated with cancer cell invasion, metastasis, and certain neurodegenerative disorders like Alzheimer's disease (Aguilar et al., 2017). Small molecules like ZCL278 have been developed to bind this interface, effectively preventing ITSN1 from activating Cdc42 and thereby inhibiting downstream oncogenic processes (Friesland et al., 2013). Targeting this protein-protein interaction provides a more selective approach than broad GTPase inhibition, potentially reducing off-target effects in clinical applications.

Other names

Cdc42-ITSN interfaceCdc42-Intersectin-1 interaction siteCdc42 Switch I-ITSN1 DH domain interfaceCdc42-ITSN1 complex

Small molecule inhibition of the interaction between Cdc42 and its guanine nucleotide exchange factor (GEF) Intersectin-1, preventing the exchange of GDP for GTP and thus maintaining Cdc42 in an inactive state (Friesland et al., 2013).