9G6E

CLC7(Y715C)/OSTM1 complex

9G6E の概要

• エントリーDOI: 10.2210/pdb9g6e/pdb
• EMDBエントリー: 51099
• 分子名称: H(+)/Cl(-) exchange transporter 7, Osteopetrosis-associated transmembrane protein 1, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• 機能のキーワード: lysosomal transporter, ph regulation, membrane complex, transporter, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 258057.06

構造登録者

Lin, Y.,Deme, J.C.,Lea, S.M.,Newstead, S. (登録日: 2024-07-18, 公開日: 2025-07-30, 最終更新日: 2025-12-10)

主引用文献

Hilton, J.K.,Lin, Y.,Sefah, E.,Deme, J.C.,Parker, J.L.,Langton, M.J.,Grabe, M.,Lea, S.,Newstead, S.,Mindell, J.A.
Mechanism of phosphoinositide regulation of lysosomal pH via inhibition of CLC-7.
Biorxiv, 2025

PubMed Abstract: Lysosomes process cellular waste and coordinate responses to metabolic challenge. Central to lysosomal homeostasis are phosphoinositide lipids, key signaling molecules which establish organelle identity, regulate membrane dynamics and are tightly linked to the pathophysiology and therapy of lysosomal storage disorders, neurodegeneration, and cancer. Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) interacts with multiple lysosomal membrane proteins and plays a critical role in regulating lysosomal pH by directly inhibiting the chloride/proton antiporter ClC-7, though the molecular mechanism of this inhibition remains unclear. Here, using a combination of functional, structural, and computational analysis, we demonstrate that PI(3,5)P2 binding dramatically remodels the structure of ClC-7 by inducing close association between cytosolic and transmembrane domains. Disease-causing mutations show increased transport activity through loss of PI(3,5)P2 binding and subsequent inhibition. Conversely, ClC-7 activation is correlated with dissociation and increased disorder of the cytoplasmic domain along with novel transmembrane domain conformations, revealing a mechanistic link between specific lysosomal lipids, transporter regulation, and the enigmatic basis of the ClC-7 slow gate.

PubMed: 41256531
DOI: 10.1101/2025.10.01.679551

実験手法

ELECTRON MICROSCOPY (2.6 Å)