The globular tail domain puts on the brake to stop the ATPase cycle of myosin Va.
Myosin Va is a well known processive motor involved in transport of organelles. A tail-inhibition model is generally accepted for the regulation of myosin Va: inhibited myosin Va is in a folded conformation such that the tail domain interacts with and inhibits myosin Va motor activity. Recent studies indicate that it is the C-terminal globular tail domain (GTD) that directly inhibits the motor activity of myosin Va. In the present study, we identified a conserved acidic residue in the motor domain (Asp-136) and two conserved basic residues in the GTD (Lys-1706 and Lys-1779) as critical residues for this regulation. Alanine mutations of these conserved charged residues not only abolished the inhibition of motor activity by the GTD but also prevented myosin Va from forming a folded conformation. We propose that Asp-136 forms ionic interactions with Lys-1706 and Lys-1779. This assignment locates the GTD-binding site in a pocket of the motor domain, formed by the N-terminal domain, converter, and the calmodulin in the first IQ motif. We propose that binding of the GTD to the motor domain prevents the movement of the converter/lever arm during ATP hydrolysis cycle, thus inhibiting the chemical cycle of the motor domain.
Li
Xiang-Dong
XD
Departments of Physiology and Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Jung
Hyun Suk
HS
Wang
Qizhi
Q
Ikebe
Reiko
R
Craig
Roger
R
Ikebe
Mitsuo
M
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D002645:Chickens; D017124:Conserved Sequence / Q000235:genetics; D008239:Lysine / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D018995:Myosin Heavy Chains / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D024701:Myosin Type V / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics
C513082:Myo5a protein, mouse; D001224:Aspartic Acid; D000251:Adenosine Triphosphatases; D024701:Myosin Type V; D018995:Myosin Heavy Chains; D008239:Lysine; D000409:Alanine