title: Actin is the primary cellular receptor of bistramide A.
abstract: 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) delta, leading to the view that PKCdelta is the principal mediator of antiproliferative activity of this natural product. Contrary to this observation, we established that bistramide A binds PKCdelta with low affinity, does not activate this kinase in vitro and does not translocate GFP-PKCdelta. 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 synthetic9 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.
authors.affiliation: Department of Chemistry, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Statsuk
authors.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Baryza
authors.forename: Vishal A
authors.initials: VA
authors.lastname: Verma
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wender
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kozmin
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000199:Actins / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008968:Molecular Conformation; D051745:Protein Kinase C-delta / Q000187:drug effects / Q000378:metabolism; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000081:Acetamides; D000199:Actins; D011714:Pyrans; D013141:Spiro Compounds; C059975:bistratene A; D051745:Protein Kinase C-delta