Profilin-1 – actin binding interface (PFN1-actin interface) (PFN1)

Profilin-1 (PFN1) is a ubiquitous actin-binding protein that plays a critical role in regulating the dynamics of the actin cytoskeleton by promoting the exchange of ADP for ATP on G-actin and facilitating its polymerization (UniProt: P07602). The Profilin-1 – actin binding interface is a specific structural site where PFN1 interacts with monomeric actin, a process essential for cell motility, cytokinesis, and intracellular signaling (Hao et al., JBC, 2016). In pathology, mutations in the PFN1 gene are a known cause of familial amyotrophic lateral sclerosis (ALS), leading to protein aggregation and cytoskeletal defects (Wu et al., Nature, 2012). Additionally, overexpression of PFN1 is associated with vascular hypertrophy in hypertension and atherosclerosis, while its dysregulation is implicated in various cancers (Romeo et al., J. Hypertens., 2007). Therapeutic strategies targeting this interface aim to modulate actin polymerization using small molecule inhibitors to treat cardiovascular diseases or prevent the toxic aggregation seen in neurodegenerative disorders. However, because actin is fundamental to nearly all cellular processes, achieving selectivity and avoiding systemic toxicity remain significant challenges in drug development. Current research focuses on identifying disease-specific conformational states of the interface to improve the safety and efficacy of potential therapeutics.

Other names

PFN1Profilin-1Actin-binding protein Profilin-1PFN1-actin interface

Inhibition of the interaction between Profilin-1 and monomeric G-actin to modulate actin filament assembly and cellular contractility.