4X25

Structural basis for mutation-induced destabilization of Profilin 1 in ALS

4X25 の概要

• エントリーDOI: 10.2210/pdb4x25/pdb
• 関連するPDBエントリー: 4X1L 4X1M
• 分子名称: Profilin-1 (2 entities in total)
• 機能のキーワード: human profilin-1 m114t mutant als, protein binding
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytoskeleton: P07737
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30082.26

構造登録者

Silvas, T.V.,Shandilya, S.M.D.,Schiffer, C.A. (登録日: 2014-11-25, 公開日: 2015-06-10, 最終更新日: 2024-02-28)

主引用文献

Boopathy, S.,Silvas, T.V.,Tischbein, M.,Jansen, S.,Shandilya, S.M.,Zitzewitz, J.A.,Landers, J.E.,Goode, B.L.,Schiffer, C.A.,Bosco, D.A.
Structural basis for mutation-induced destabilization of profilin 1 in ALS.
Proc. Natl. Acad. Sci. U.S.A., 112:7984-7989, 2015

PubMed 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.

PubMed: 26056300
DOI: 10.1073/pnas.1424108112

実験手法

X-RAY DIFFRACTION (2.23 Å)