Dynamin pleckstrin homology domain (Dynamin PH domain)

The Dynamin pleckstrin homology (PH) domain is a specialized protein module within the dynamin GTPase family, primarily responsible for targeting the enzyme to the plasma membrane by binding to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (UniProt: Q05193). This interaction is essential for the recruitment of dynamin to the necks of budding vesicles, where it oligomerizes to facilitate membrane scission during clathrin-mediated endocytosis (PubMed: 10652310). Beyond its role in vesicle trafficking, the PH domain also interacts with the actin cytoskeleton and various signaling proteins, making it a central hub for cellular remodeling. In clinical contexts, mutations in the PH domain of Dynamin-2 are linked to neuromuscular disorders such as Charcot-Marie-Tooth disease and centronuclear myopathy (PubMed: 16227997). Furthermore, because dynamin is often hijacked by viruses for cellular entry and is overexpressed in several cancers, the PH domain has emerged as a viable therapeutic target. Small molecule inhibitors like MiTMAB and Dyngo-4a specifically target this domain to disrupt lipid binding, offering a strategy to block endocytosis-dependent processes in disease (PubMed: 21524197). However, the high conservation of PH domains across different proteins poses a challenge for achieving high drug specificity and minimizing off-target effects.

Other names

PH domain of dynaminDNM-PH domainPleckstrin homology domain of DNM1Pleckstrin homology domain of DNM2

Inhibition of the interaction between the pleckstrin homology domain and membrane phosphoinositides, specifically phosphatidylinositol 4,5-bisphosphate (PIP2), which prevents the recruitment of dynamin to the plasma membrane and inhibits vesicle scission.