Choline acetyltransferase structure reveals distribution of mutations that cause motor disorders.
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.
Cai
Yiying
Y
Department of Molecular and Cellular Biochemistry, and Center for Structural Biology, University of Kentucky, Lexington, KY 40536, USA.
Cronin
Ciarán N
CN
Engel
Andrew G
AG
Ohno
Kinji
K
Hersh
Louis B
LB
Rodgers
David W
DW
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002795:Choline O-Acetyltransferase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D003065:Coenzyme A / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009069:Movement Disorders / Q000151:congenital / Q000201:enzymology* / Q000235:genetics*; D009154:Mutation; D011487:Protein Conformation; D051381:Rats; D016415:Sequence Alignment
D002795:Choline O-Acetyltransferase; D003065:Coenzyme A