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Structure-function relationships of the alpha/beta-hydrolase fold domain of neuroligin: a comparison with acetylcholinesterase.

Abstract
The neuroligins are postsynaptic cell adhesion proteins whose extracellular domain belongs to the alpha/beta-hydrolase fold family of proteins, a family characterized through the enzyme acetylcholinesterase (AChE) and other enzymes with various substrate specificities. Neuroligin associations with the pre-synaptic neurexins participate in synapse maturation and maintenance. Alternative splicing of the neuroligin and neurexin genes results in multiple isoforms and presumably regulation of activity, while mutations appear to be associated with autism spectrum disorders. The crystal structures of the extracellular, cell adhesion domain of three neuroligins (NL1, NL2 and NL4) revealed features that distinguish the neuroligins from their enzyme relatives and could not be predicted by homology modelling from an AChE template. The structures of NL1 and NL4 bound with a soluble beta-neurexin domain (Nrxbeta1) revealed the precise position and orientation of the bound Nrxbeta1 and the Ca(2+)-dependent interaction network at the complex interface. Herein we present an overview of the unbound and Nrxbeta1-bound neuroligin structures and compare them with structures of AChEs with and without a bound fasciculin partner. This study exemplifies how an alpha/beta-hydrolase fold domain tailored for catalysis varies to acquire adhesion properties, and defines three surface regions with distinctive locations and properties for homologous or heterologous partner association.
AuthorsPhilippe Leone, Davide Comoletti, Palmer Taylor, Yves Bourne, Pascale Marchot
JournalChemico-biological interactions (Chem Biol Interact) Vol. 187 Issue 1-3 Pg. 49-55 (Sep 06 2010) ISSN: 1872-7786 [Electronic] Ireland
PMID20100470 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Cell Adhesion Molecules, Neuronal
  • Elapid Venoms
  • Ligands
  • fasciculin
  • Acetylcholinesterase
  • Cysteine
  • Calcium
Topics
  • Acetylcholinesterase (chemistry, metabolism)
  • Amino Acid Sequence
  • Animals
  • Calcium (metabolism)
  • Catalytic Domain
  • Cell Adhesion Molecules, Neuronal (chemistry, genetics, metabolism)
  • Cysteine
  • Elapid Venoms (metabolism)
  • Humans
  • Ligands
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Point Mutation
  • Protein Structure, Tertiary
  • Rats
  • Selection, Genetic
  • Structure-Activity Relationship

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