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Structural requirements for VAP-B oligomerization and their implication in amyotrophic lateral sclerosis-associated

SoHui Kim1, Sónia S Leal, Daniel Ben Halevy

  • 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.

The Journal of Biological Chemistry
|March 9, 2010
PubMed

Insights

A mutation in VAP-B protein causes familial motor neuron diseases by forming toxic aggregates. This study reveals how the P56S mutation in VAP-B protein leads to aggregation and neurotoxicity.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Protein Biochemistry

Background:

  • Vesicle-associated membrane protein B (VAP-B) is an endoplasmic reticulum protein interacting with lipid-binding proteins via its MSP domain.
  • A P56S mutation in VAP-B is linked to familial forms of motor neuron diseases, causing insoluble protein aggregate formation through an unclear mechanism.

Purpose of the Study:

  • To elucidate the structural basis of VAP-B oligomerization.
  • To determine the role of VAP-B oligomerization in P56S-induced aggregation and neurotoxicity.

Main Methods:

  • Investigated VAP-B oligomerization using structural analysis.
  • Assessed the impact of the P56S mutation on VAP-B structure, aggregation, and neurotoxicity.

Main Results:

  • VAP-B oligomerization is primarily mediated by its coiled-coil domain; the transmembrane domain's GXXXG motif facilitates self-association but not full oligomerization.
  • The P56S mutation induces conformational changes in the MSP domain, exposing hydrophobic regions and promoting aggregation.
  • Mutant VAP-B(P56S) aggregation is driven by combined coiled-coil and transmembrane domain interactions, hindering FFAT binding and leading to neurotoxicity.

Conclusions:

  • VAP-B oligomerization is crucial for the P56S mutation's aggregation and associated neurotoxicity in familial motor neuron diseases.
  • The P56S mutation disrupts VAP-B structure, promoting aggregation and disease pathogenesis by altering protein-protein interactions.

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