Crystal structures of human pantothenate kinases: Insights into allosteric regulation and mutations linked to a neurodegeneration disorder

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

Research output: Contribution to journalArticle

Abstract

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 PanK1α 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.

Original languageEnglish (US)
Pages (from-to)27984-27993
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number38
DOIs
StatePublished - Sep 21 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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