9AYD

Mitochondrial fission 1 (Fis1) protein structure Y38E mutation 1.53A

9AYD の概要

• エントリーDOI: 10.2210/pdb9ayd/pdb
• 分子名称: Mitochondrial fission 1 protein, TRIETHYLENE GLYCOL, ACETATE ION, ... (4 entities in total)
• 機能のキーワード: fis1 structure, mitochondrial fission, drug design, unknown function
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30449.96

構造登録者

Mathews, I.I.,Pokhrel, S.,Wakatsuki, S. (登録日: 2024-03-07, 公開日: 2025-05-21)

主引用文献

Pokhrel, S.,Heo, G.,Mathews, I.,Yokoi, S.,Matsui, T.,Mitsutake, A.,Wakatsuki, S.,Mochly-Rosen, D.
A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress.
Nat Commun, 16:4187-4187, 2025

PubMed Abstract: Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.

PubMed: 40328741
DOI: 10.1038/s41467-025-59434-6

実験手法

X-RAY DIFFRACTION (1.53 Å)