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J. Biol. Chem., Vol. 281, Issue 5, 2876-2881, February 3, 2006

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Structure of the N-terminal Calcium Sensor Domain of Centrin Reveals the Biochemical Basis for Domain-specific Function^*

Jonathan H. Sheehan¹, Christopher G. Bunick¹, Haitao Hu¹², Patricia A. Fagan¹, Susan M. Meyn, and Walter J. Chazin³

From the Departments of Biochemistry and Physics and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232-8725 and the Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92307

Centrin is an essential component of microtubule-organizing centers in organisms ranging from algae and yeast to humans. It is an EF-hand calcium-binding protein with homology to calmodulin but distinct calcium binding properties. In a previously proposed model, the C-terminal domain of centrin serves as a constitutive anchor to target proteins, and the N-terminal domain serves as the sensor of calcium signals. The three-dimensional structure of the N-terminal domain of Chlamydomonas rheinhardtii centrin has been determined in the presence of calcium by solution NMR spectroscopy. The domain is found to occupy an open conformation typical of EF-hand calcium sensors. Comparison of the N- and C-terminal domains of centrin reveals a structural and biochemical basis for the domain specificity of interactions with its cellular targets and the distinct nature of centrin relative to other EF-hand proteins. An NMR titration of the centrin N-terminal domain with a fragment of the known centrin target Sfi1 reveals binding of the peptide to a discrete site on the protein, which supports the proposal that the N-terminal domain serves as a calcium sensor in centrin.

Received for publication, September 8, 2005 , and in revised form, November 28, 2005.

The atomic coordinates and structure factors (code 2AMI) 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 by Operating Grants RO1 GM-40120 and GM-65484 (to W. J. C.) and Vanderbilt Center in Molecular Toxicology Grant P30 ES0000267 (for facilities) from the National Institutes of Health. 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.

¹ These authors contributed equally to this research.

² Present address: Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Indianapolis, IN 46285.

³ To whom correspondence should be addressed. Tel.: 615-936-2210; Fax: 615-936-2211; walter.chazin{at}vanderbilt.edu.

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