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ALS-causing P56S mutation and splicing variation on the hVAPB MSP domain transform its β-sandwich fold into

Haina Qin1, Wei Wang, Jianxing Song

  • 1Department of Biological Sciences, Faculty of Science, Yong Loo Lin School of Medicine and National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore.

Biochemical and Biophysical Research Communications
|January 22, 2013
PubMed

Insights

A mutation in the VAPB protein causes familial ALS by altering its structure. In membranes, the mutated protein becomes helical, potentially explaining its disease mechanism before aggregation.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Molecular Biology

Background:

  • The P56S mutation in the VAPB protein's MSP domain is linked to familial Amyotrophic Lateral Sclerosis (ALS).
  • Previous studies indicated that P56S mutation causes the MSP domain to be predominantly disordered in aqueous solutions.
  • ALS is a progressive neurodegenerative disease affecting nerve cells in the brain and spinal cord.

Purpose of the Study:

  • To investigate the structural transformation of the VAPB P56S-MSP domain in a membrane environment.
  • To explore the structural behavior of a VAPB splicing variant (VAPB-3) with a truncated MSP domain.
  • To elucidate the mechanism by which VAPB mutations/variants contribute to ALS pathogenesis.

Main Methods:

  • Nuclear Magnetic Resonance (NMR) spectroscopy to determine protein structure.
  • In vitro studies to assess protein aggregation and solubility.
  • Analysis of protein conformation in different environments (water vs. membrane).

Main Results:

  • The P56S-MSP domain unexpectedly adopts a highly helical conformation within a membrane environment.
  • This conformational change, termed 'chameleon transformation', was also observed in the truncated VAPB-3 variant.
  • VAPB-3 was found to be highly disordered and insoluble in buffer, as confirmed by NMR.
  • The findings suggest a novel function for VAPB mutants/variants in mediating ER structure prior to significant aggregate formation.

Conclusions:

  • The VAPB P56S mutation induces a significant conformational change in response to the membrane environment.
  • This structural plasticity may represent an early mechanism in ALS pathogenesis.
  • Understanding these conformational dynamics is crucial for developing therapeutic strategies for VAPB-related ALS.

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