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J. Biol. Chem., Vol. 282, Issue 1, 667-679, January 5, 2007

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Structural Basis for the Interaction of the Myosin Light Chain Mlc1p with the Myosin V Myo2p IQ Motifs^*

Matteo Pennestri, Sonia Melino, Gian Marco Contessa, Elena Caroli Casavola¹, Maurizio Paci, Antonella Ragnini-Wilson, and Daniel O. Cicero²

From the Departments of Chemical Science and Technology and Biology, Università di Roma "Tor Vergata," Via della Ricerca Scientifica 1, 00133 Rome, Italy

Calmodulin, regulatory, and essential myosin light chain are evolutionary conserved proteins that, by binding to IQ motifs of target proteins, regulate essential intracellular processes among which are efficiency of secretory vesicles release at synapsis, intracellular signaling, and regulation of cell division. The yeast Saccharomyces cerevisiae calmodulin Cmd1 and the essential myosin light chain Mlc1p share the ability to interact with the class V myosin Myo2p and Myo4 and the class II myosin Myo1p. These myosins are required for vesicle, organelle, and mRNA transport, spindle orientation, and cytokinesis. We have used the budding yeast model system to study how calmodulin and essential myosin light chain selectively regulate class V myosin function. NMR structural analysis of uncomplexed Mlc1p and interaction studies with the first three IQ motifs of Myo2p show that the structural similarities between Mlc1p and the other members of the EF-hand superfamily of calmodulin-like proteins are mainly restricted to the C-lobe of these proteins. The N-lobe of Mlc1p presents a significantly compact and stable structure that is maintained both in the free and complexed states. The Mlc1p N-lobe interacts with the IQ motif in a manner that is regulated both by the IQ motifs sequence as well as by light chain structural features. These characteristic allows a distinctive interaction of Mlc1p with the first IQ motif of Myo2p when compared with calmodulin. This finding gives us a novel view of how calmodulin and essential light chain, through a differential binding to IQ1 of class V myosin motor, regulate this activity during vegetative growth and cytokinesis.

Received for publication, July 24, 2006 , and in revised form, October 25, 2006.

The atomic coordinates and structure factors (code 2FCD and 2FCE) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by the Telethon Foundation-Italy and by funds of the Ministero dell'Istruzione dell'Università e della Ricerca (PRIN programs) and FIRB (programs for basic research). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ Supported by a Telethon Ph.D. fellowship from Grant GGP030341.

² To whom correspondence should be addressed: Dept. of Chemical Science and Technology, Università di Roma "Tor Vergata" Via della Ricerca Scientifica 1, 00133 Rome, Italy. Tel.: 39-06-72594835; Fax: 39-06-72594328; E-mail: cicero{at}scienze.uniroma2.it.

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