Title

Human deafness mutation of myosin VI (C442Y) accelerates the ADP dissociation rate

UMMS Affiliation

Department of Physiology

Date

5-5-2004

Document Type

Article

Subjects

Actins; Adenosine Diphosphate; Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Calcium; Deafness; Humans; Mice; Molecular Motor Proteins; *Mutation, Missense; Myosin Heavy Chains; Protein Binding; Tryptophan

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

The missense mutation of Cys(442) to Tyr of myosin VI causes progressive postlingual sensorineural deafness. Here we report the affects of the C442Y mutation on the kinetics of the actomyosin ATP hydrolysis mechanism and motor function of myosin VI. The largest changes in the kinetic mechanism of ATP hydrolysis produced by the C442Y mutation are about 10-fold increases in the rate of ADP dissociation from both myosin VI and actomyosin VI. The rates of ADP dissociation from acto-C442Y myosin VI-ADP and C442Y myosin VI-ADP are 20-40 times more rapid than the steady state rates and cannot be the rate-limiting steps of the hydrolysis mechanism in the presence or absence of actin. The 2-fold increase in the actin gliding velocity of C442Y compared with wild type (WT) may be explained at least in part by the more rapid rate of ADP dissociation. The C442Y myosin VI has a significant increase ( approximately 10-fold) in the steady state ATPase rate in the absence of actin relative to WT myosin VI. The steady state rate of actin-activated ATP hydrolysis is unchanged by the C442Y mutation at low (<10(-7) m) calcium but is calcium-sensitive with a 1.6-fold increase at high ( approximately 10(-4) m) calcium that does not occur with WT. The actin gliding velocity of the C442Y mutant decreases significantly at low surface density of myosin VI, suggesting that the mutation hampers the processive movement of myosin VI.

Rights and Permissions

Citation: J Biol Chem. 2004 Jul 9;279(28):28844-54. Epub 2004 Apr 29. Link to article on publisher's site

DOI of Published Version

10.1074/jbc.M314332200

Related Resources

Link to Article in PubMed

Journal Title

The Journal of biological chemistry

PubMed ID

15123708