Choline acetyltransferase structure reveals distribution of mutations that cause motor

Yiying Cai, Ciarán N. Cronin, Andrew G. Engel, Kinji Ohno, Louis B. Hersh, David W. Rodgers

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Choline acetyltransferase (ChAT) synthesizes acetylcholine in neurons and other cell types. Decreases in ChAT activity are associated with a number of disease states, and mutations in ChAT cause congenital neuromuscular disorders. The crystal structure of ChAT reported here shows the enzyme divided into two domains with the active site in a solvent accessible tunnel at the domain interface. A low-resolution view of the complex with one substrate, coenzyme A, defines its binding site and suggests an additional interaction not found in the related carnitine acetyltransferase. Also, the preference for choline over carnitine as an acetyl acceptor is seen to result from both electrostatic and steric blocks to carnitine binding at the active site. While half of the mutations that cause motor disorders are positioned to affect enzyme activity directly, the remaining changes are surprisingly distant from the active site and must exert indirect effects. The structure indicates how ChAT is regulated by phosphorylation and reveals an unusual pattern of basic surface patches that may mediate membrane association or macromolecular interactions.

Original languageEnglish (US)
Pages (from-to)2047-2058
Number of pages12
JournalEMBO Journal
Volume23
Issue number10
DOIs
StatePublished - May 19 2004

Keywords

  • Acetyltransferase
  • Cholinergic
  • Crystal structure
  • Myasthenic syndrome
  • Neurotransmission

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Fingerprint Dive into the research topics of 'Choline acetyltransferase structure reveals distribution of mutations that cause motor'. Together they form a unique fingerprint.

  • Cite this