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J. Biol. Chem., Vol. 282, Issue 38, 27984-27993, September 21, 2007

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Crystal Structures of Human Pantothenate Kinases

INSIGHTS INTO ALLOSTERIC REGULATION AND MUTATIONS LINKED TO A NEURODEGENERATION DISORDER^*

Bum Soo Hong, Guillermo Senisterra, Wael M. Rabeh, Masoud Vedadi, Roberta Leonardi, Yong-Mei Zhang, Charles O. Rock, Suzanne Jackowski, and Hee-Won Park^¶1

From the Structural Genomics Consortium and ^¶Department of Pharmacology, University of Toronto, Toronto, Ontario M5G 1L5, Canada and the Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794

Pantothenate kinase (PanK) catalyzes the first step in CoA biosynthesis and there are three human genes that express four isoforms with highly conserved catalytic core domains. Here we report the homodimeric structures of the catalytic cores of PanK1 and PanK3 in complex with acetyl-CoA, a feedback inhibitor. Each monomer adopts a fold of the actin kinase superfamily and the inhibitor-bound structures explain the basis for the allosteric regulation by CoA thioesters. These structures also provide an opportunity to investigate the structural effects of the PanK2 mutations that have been implicated in neurodegeneration. Biochemical and thermodynamic analyses of the PanK3 mutant proteins corresponding to PanK2 mutations show that mutant proteins with compromised activities and/or stabilities correlate with a higher incidence of the early onset of disease.

Received for publication, March 5, 2007 , and in revised form, July 12, 2007.

The atomic coordinates and structure factors (code 2I7N and 2I7P) 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 the Structural Genomics Consortium with funds from Genome Canada through the Ontario Genomics Institute, the Canadian Institutes for Health Research, the Canada Foundation for Innovation, the Ontario Research and Development Challenge Fund, the Ontario Innovation Trust, the Wellcome Trust, GlaxoSmithKline, the Knut and Alice Wallenberg Foundation, Vinnova, the Swedish Foundation for Strategic Research, National Institutes of Health Grants GM62896 and GM34496, Cancer Center (CORE) Support Grant CA21765, and the American Lebanese Syrian Associated Charities. Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-06CH11357. 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 Figs. S1–S4 and Table S1.

¹ To whom correspondence may be addressed. Tel.: 416-946-3867; Fax: 416-946-0880; E-mail: heewon.park{at}utoronto.ca.

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