2fy5
Structures of ligand bound human choline acetyltransferase provide insight into regulation of acetylcholine synthesis
Structural highlights
DiseaseCLAT_HUMAN Defects in CHAT are the cause of congenital myasthenic syndrome with episodic apnea (CMSEA) [MIM:254210; formerly known as familial infantile myasthenia gravis 2 (FIMG2). CMSEA is an autosomal recessive congenital myasthenic syndrome. Patients have myasthenic symptoms since birth or early infancy, negative tests for anti-AChR antibodies, and abrupt episodic crises with increased weakness, bulbar paralysis, and apnea precipitated by undue exertion, fever, or excitement.[1] [2] FunctionCLAT_HUMAN Catalyzes the reversible synthesis of acetylcholine (ACh) from acetyl CoA and choline at cholinergic synapses. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedCholine acetyltransferase (ChAT) catalyzes the synthesis of the neurotransmitter acetylcholine from choline and acetyl-CoA, and its presence is a defining feature of cholinergic neurons. We report the structure of human ChAT to a resolution of 2.2 A along with structures for binary complexes of ChAT with choline, CoA, and a nonhydrolyzable acetyl-CoA analogue, S-(2-oxopropyl)-CoA. The ChAT-choline complex shows which features of choline are important for binding and explains how modifications of the choline trimethylammonium group can be tolerated by the enzyme. A detailed model of the ternary Michaelis complex fully supports the direct transfer of the acetyl group from acetyl-CoA to choline through a mechanism similar to that seen in the serine hydrolases for the formation of an acyl-enzyme intermediate. Domain movements accompany CoA binding, and a surface loop, which is disordered in the unliganded enzyme, becomes localized and binds directly to the phosphates of CoA, stabilizing the complex. Interactions between this surface loop and CoA may function to lower the KM for CoA and could be important for phosphorylation-dependent regulation of ChAT activity. Substrate binding and catalytic mechanism of human choline acetyltransferase.,Kim AR, Rylett RJ, Shilton BH Biochemistry. 2006 Dec 12;45(49):14621-31. PMID:17144655[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
