Actin is the primary cellular receptor of bistramide A

• Published in: Nature chemical biology Vol. 1; no. 7; pp. 383 - 388
• Main Authors: Kozmin, Sergey A, Statsuk, Alexander V, Bai, Ruoli, Baryza, Jeremy L, Verma, Vishal A, Hamel, Ernest, Wender, Paul A
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2005
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Actins - drug effects; Actins - metabolism; Animals; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Cytoskeleton - drug effects; Cytoskeleton - metabolism; Humans; In Vitro Techniques; Molecular Conformation; Protein Kinase C-delta - drug effects; Protein Kinase C-delta - metabolism; Pyrans - chemical synthesis; Pyrans - chemistry; Pyrans - pharmacology; Rats; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Time Factors
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio748

Bistramide A (1) is a marine natural product with broad, potent antiproliferative effects. Bistramide A has been reported to selectively activate protein kinase C (PKC) δ, leading to the view that PKCδ is the principal mediator of antiproliferative activity of this natural product. Contrary to this observation, we established that bistramide A binds PKCδ with low affinity, does not activate this kinase in vitro and does not translocate GFP-PKCδ. Furthermore, we identified actin as the cellular receptor of bistramide A. We report that bistramide A disrupts the actin cytoskeleton, inhibits actin polymerization, depolymerizes filamentous F-actin in vitro and binds directly to monomeric G-actin in a 1:1 ratio with a Kd of 7 nM. We also constructed a fully synthetic bistramide A-based affinity matrix and isolated actin as a specific bistramide A-binding protein. This activity provides a molecular explanation for the potent antiproliferative effects of bistramide A, identifying it as a new biochemical tool for studies of the actin cytoskeleton and as a potential lead for development of a new class of antitumor agents.