Structure of GABARAP in two conformations: implications for GABA(A) receptor localization and tubulin binding

Neuron. 2002 Jan 3;33(1):63-74. doi: 10.1016/s0896-6273(01)00558-x.

Abstract

GABARAP recognizes and binds the gamma2 subunit of the GABA(A) receptor, interacts with microtubules and the N-ethyl maleimide sensitive factor, and is proposed to function in GABA(A) receptor trafficking and postsynaptic localization. We have determined the crystal structure of human GABARAP at 1.6 A resolution. The structure comprises an N-terminal helical subdomain and a ubiquitin-like C-terminal domain. Structure-based mutational analysis demonstrates that the N-terminal subdomain is responsible for tubulin binding while the C-terminal domain contains the binding site for the GABA(A). A second GABARAP crystal form was determined at 1.9 A resolution and documents that GABARAP can self-associate in a head-to-tail manner. The structural details of this oligomerization reveal how GABARAP can both promote tubulin polymerization and facilitate GABA(A) receptor clustering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis Regulatory Proteins
  • Binding Sites / physiology
  • Humans
  • Microtubule-Associated Proteins / chemistry*
  • Microtubules / metabolism*
  • Molecular Sequence Data
  • Neural Inhibition / physiology*
  • Polymers / metabolism
  • Protein Structure, Tertiary / physiology
  • Protein Transport / physiology*
  • Receptors, GABA-A / metabolism*
  • Sequence Homology, Amino Acid
  • Synaptic Membranes / metabolism
  • Synaptic Transmission / physiology*
  • Tubulin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • GABARAP protein, human
  • Microtubule-Associated Proteins
  • Polymers
  • Receptors, GABA-A
  • Tubulin