1vzj

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1vzj, resolution 2.35Å ()
Non-Standard Residues:
Activity: Acetylcholinesterase, with EC number 3.1.1.7
Related: 1b41, 1f8u, 2clj
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

STRUCTURE OF THE TETRAMERIZATION DOMAIN OF ACETYLCHOLINESTERASE: FOUR-FOLD INTERACTION OF A WWW MOTIF WITH A LEFT-HANDED POLYPROLINE HELIX

Publication Abstract from PubMed

Functional localization of acetylcholinesterase (AChE) in vertebrate muscle and brain depends on interaction of the tryptophan amphiphilic tetramerization (WAT) sequence, at the C-terminus of its major splice variant (T), with a proline-rich attachment domain (PRAD), of the anchoring proteins, collagenous (ColQ) and proline-rich membrane anchor. The crystal structure of the WAT/PRAD complex reveals a novel supercoil structure in which four parallel WAT chains form a left-handed superhelix around an antiparallel left-handed PRAD helix resembling polyproline II. The WAT coiled coils possess a WWW motif making repetitive hydrophobic stacking and hydrogen-bond interactions with the PRAD. The WAT chains are related by an approximately 4-fold screw axis around the PRAD. Each WAT makes similar but unique interactions, consistent with an asymmetric pattern of disulfide linkages between the AChE tetramer subunits and ColQ. The P59Q mutation in ColQ, which causes congenital endplate AChE deficiency, and is located within the PRAD, disrupts crucial WAT-WAT and WAT-PRAD interactions. A model is proposed for the synaptic AChE(T) tetramer.

The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix., Dvir H, Harel M, Bon S, Liu WQ, Vidal M, Garbay C, Sussman JL, Massoulie J, Silman I, EMBO J. 2004 Nov 10;23(22):4394-405. Epub 2004 Nov 4. PMID:15526038

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[COLQ_HUMAN] Defects in COLQ are the cause of congenital myasthenic syndrome Engel type (CMSE) [MIM:603034]; also known as end-plate acetylcholinesterase deficiency or congenital myasthenic syndrome type IC (CMS-IC). CMSE is a rare autosomal recessive congenital myasthenic syndrome characterized by onset during childhood, generalized weakness, abnormal fatigability on exertion, refrectoriness to acetylcholinesterase drugs, decremental electromyographic response and morphological abnormalities of the neuromuscular junctions.[1][2]

Function

[ACES_HUMAN] Terminates signal transduction at the neuromuscular junction by rapid hydrolysis of the acetylcholine released into the synaptic cleft. Role in neuronal apoptosis.[3][4][5][6] [COLQ_HUMAN] Anchors the catalytic subunits of asymmetric AChE to the synaptic basal lamina.

About this Structure

1vzj is a 10 chain structure. Full crystallographic information is available from OCA.

See Also

Reference

  • Dvir H, Harel M, Bon S, Liu WQ, Vidal M, Garbay C, Sussman JL, Massoulie J, Silman I. The synaptic acetylcholinesterase tetramer assembles around a polyproline II helix. EMBO J. 2004 Nov 10;23(22):4394-405. Epub 2004 Nov 4. PMID:15526038 doi:7600425
  1. Donger C, Krejci E, Serradell AP, Eymard B, Bon S, Nicole S, Chateau D, Gary F, Fardeau M, Massoulie J, Guicheney P. Mutation in the human acetylcholinesterase-associated collagen gene, COLQ, is responsible for congenital myasthenic syndrome with end-plate acetylcholinesterase deficiency (Type Ic). Am J Hum Genet. 1998 Oct;63(4):967-75. PMID:9758617
  2. Ohno K, Engel AG, Brengman JM, Shen XM, Heidenreich F, Vincent A, Milone M, Tan E, Demirci M, Walsh P, Nakano S, Akiguchi I. The spectrum of mutations causing end-plate acetylcholinesterase deficiency. Ann Neurol. 2000 Feb;47(2):162-70. PMID:10665486
  3. Chhajlani V, Derr D, Earles B, Schmell E, August T. Purification and partial amino acid sequence analysis of human erythrocyte acetylcholinesterase. FEBS Lett. 1989 Apr 24;247(2):279-82. PMID:2714437
  4. Velan B, Grosfeld H, Kronman C, Leitner M, Gozes Y, Lazar A, Flashner Y, Marcus D, Cohen S, Shafferman A. The effect of elimination of intersubunit disulfide bonds on the activity, assembly, and secretion of recombinant human acetylcholinesterase. Expression of acetylcholinesterase Cys-580----Ala mutant. J Biol Chem. 1991 Dec 15;266(35):23977-84. PMID:1748670
  5. Shafferman A, Kronman C, Flashner Y, Leitner M, Grosfeld H, Ordentlich A, Gozes Y, Cohen S, Ariel N, Barak D, et al.. Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding. J Biol Chem. 1992 Sep 5;267(25):17640-8. PMID:1517212
  6. Yang L, He HY, Zhang XJ. Increased expression of intranuclear AChE involved in apoptosis of SK-N-SH cells. Neurosci Res. 2002 Apr;42(4):261-8. PMID:11985878

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