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TitleMechanism of phosphoinositide regulation of lysosomal pH via inhibition of CLC-7.
Journal, issue, pagesbioRxiv, Year 2025
Publish dateOct 2, 2025
AuthorsJacob K Hilton / Yifei Lin / Eric Sefah / Justin C Deme / Joanne L Parker / Matthew J Langton / Michael Grabe / Susan Lea / Simon Newstead / Joseph A Mindell /
PubMed AbstractLysosomes process cellular waste and coordinate responses to metabolic challenge. Central to lysosomal homeostasis are phosphoinositide lipids, key signaling molecules which establish organelle ...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.
External linksbioRxiv / PubMed:41256531 / PubMed Central
MethodsEM (single particle)
Resolution1.8 - 2.7 Å
Structure data

51097

9g6c

EMDB-51097, PDB-9g6c:
CLC7/OSTM1 complex with bound PIP2 lipid
Method: EM (single particle) / Resolution: 1.8 Å

51098

9g6d

EMDB-51098, PDB-9g6d:
CLC7/OSTM1 complex in the absence of PIP2 lipid.
Method: EM (single particle) / Resolution: 2.7 Å

51099

9g6e

EMDB-51099, PDB-9g6e:
CLC7(Y715C)/OSTM1 complex
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-CL:
Unknown entry

PDB-1iit:
GLUR0 LIGAND BINDING CORE COMPLEX WITH L-SERINE

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Lysosomal transporter / pH Regulation / Membrane Complex / Transporter

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