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 Citations (Scopus)

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

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Choline O-Acetyltransferase
Mutation
Catalytic Domain
Carnitine
Carnitine O-Acetyltransferase
Acetylcarnitine
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Phosphorylation
Enzyme activity
Enzymes
Coenzyme A
Choline
Static Electricity
Acetylcholine
Neurons
Electrostatics
Tunnels
Crystal structure
Binding Sites
Association reactions

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Choline acetyltransferase structure reveals distribution of mutations that cause motor. / Cai, Yiying; Cronin, Ciarán N.; Engel, Andrew G; Ohno, Kinji; Hersh, Louis B.; Rodgers, David W.

In: EMBO Journal, Vol. 23, No. 10, 19.05.2004, p. 2047-2058.

Research output: Contribution to journalArticle

Cai, Yiying ; Cronin, Ciarán N. ; Engel, Andrew G ; Ohno, Kinji ; Hersh, Louis B. ; Rodgers, David W. / Choline acetyltransferase structure reveals distribution of mutations that cause motor. In: EMBO Journal. 2004 ; Vol. 23, No. 10. pp. 2047-2058.
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