Structural basis for mutation-induced destabilization of profilin 1 in ALS
Silvas, Tania V.
Zitzewitz, Jill A.
Landers, John E.
Goode, Bruce L.
Schiffer, Celia A.
Bosco, Daryl A.
UMass Chan AffiliationsDepartment of Biochemistry and Molecular Pharmacology
Department of Neurology
Document TypeJournal Article
KeywordsAmyotrophic Lateral Sclerosis
amyotrophic lateral sclerosis
Medicinal Chemistry and Pharmaceutics
Nervous System Diseases
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AbstractMutations 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.
SourceProc 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
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/48904
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