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Article
Structural basis for mutation-induced destabilization of profilin 1 in ALS
Schiffer Lab Publications
  • Sivakumar Boopathy, University of Massachusetts Medical School
  • Tania V. Silvas, University of Massachusetts Medical School
  • Maeve Tischbein, University of Massachusetts Medical School
  • Silvia Jansen, Brandeis University
  • Shivender Shandilya, University of Massachusetts Medical School
  • Jill A. Zitzewitz, University of Massachusetts Medical School
  • John E. Landers, University of Massachusetts Medical School
  • Bruce L. Goode, Brandeis University
  • Celia A. Schiffer, University of Massachusetts Medical School
  • Daryl A. Bosco, University of Massachusetts Medical School
UMMS Affiliation
Department of Neurology; Department of Biochemistry and Molecular Pharmacology
Publication Date
6-30-2015
Document Type
Article
Subjects
Amyotrophic Lateral Sclerosis; Cell Line; Crystallography, X-Ray; Humans; *Mutation; Neurons; Profilins; Protein Conformation; Protein Folding
Abstract
Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the destabilized M114T variant. In contrast, the E117G mutation only modestly perturbs the structure and stability of PFN1, an observation that reconciles the occurrence of this mutation in the control population. These findings suggest that a destabilized form of PFN1 underlies PFN1-mediated ALS pathogenesis.
Keywords
  • amyotrophic lateral sclerosis,
  • profilin 1,
  • protein stability,
  • X-ray crystallography,
  • protein misfolding
Rights and Permissions

Publisher PDF posted as allowed by the publisher's author rights policy at http://0-www.pnas.org.library.simmons.edu/site/aboutpnas/authorfaq.xhtml.

DOI of Published Version
10.1073/pnas.1424108112
Source
Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):7984-9. doi: 10.1073/pnas.1424108112. Epub 2015 Jun 8. Link to article on publisher's site
Related Resources
Link to Article in PubMed
PubMed ID
26056300
Citation Information
Sivakumar Boopathy, Tania V. Silvas, Maeve Tischbein, Silvia Jansen, et al.. "Structural basis for mutation-induced destabilization of profilin 1 in ALS" Vol. 112 Iss. 26 (2015) ISSN: 0027-8424 (Linking)
Available at: http://0-works.bepress.com.library.simmons.edu/celia_schiffer/129/