AI Article Synopsis
- Mutations in the ClC-7/Ostm1 ion transporter cause osteopetrosis and lysosomal storage disease, and their lysosomal location has made functional studies difficult.
- Using a mutated version of ClC-7 that reaches the plasma membrane, researchers found that specific regions of the Ostm1 β-subunit are crucial for ClC-7's ion exchange function and its trafficking to lysosomes.
- The study revealed that the ion exchange occurs with a specific stoichiometry and identified how certain mutations can impact the ion exchange process, suggesting broader implications for the understanding of ion exchange mechanisms in cellular contexts.
Article Abstract
Mutations in the ClC-7/Ostm1 ion transporter lead to osteopetrosis and lysosomal storage disease. Its lysosomal localization hitherto precluded detailed functional characterization. Using a mutated ClC-7 that reaches the plasma membrane, we now show that both the aminoterminus and transmembrane span of the Ostm1 β-subunit are required for ClC-7 Cl(-)/H(+)-exchange, whereas the Ostm1 transmembrane domain suffices for its ClC-7-dependent trafficking to lysosomes. ClC-7/Ostm1 currents were strongly outwardly rectifying owing to slow gating of ion exchange, which itself displays an intrinsically almost linear voltage dependence. Reversal potentials of tail currents revealed a 2Cl(-)/1H(+)-exchange stoichiometry. Several disease-causing CLCN7 mutations accelerated gating. Such mutations cluster to the second cytosolic cystathionine-β-synthase domain and potential contact sites at the transmembrane segment. Our work suggests that gating underlies the rectification of all endosomal/lysosomal CLCs and extends the concept of voltage gating beyond channels to ion exchangers.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117652 | PMC |
| http://dx.doi.org/10.1038/emboj.2011.137 | DOI Listing |
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- - ClC-6 and ClC-7 are intracellular proteins that help regulate chloride (Cl) and hydrogen ions (H) in late endosomes and lysosomes, but they function differently, with ClC-7 needing another protein called Ostm1 to operate properly.
- - Experiments showed that lower levels of external Cl reduce ClC-6 function, while they enhance ClC-7's activity, particularly under acidic conditions or low internal Cl levels.
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A Mathematical Model of Lysosomal Ion Homeostasis Points to Differential Effects of Cl Transport in Ca Dynamics.
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October 2019
Institute for Theoretical Biology (ITB), Charité-Universitätsmedizin Berlin, Corporate Member of the Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10115 Berlin, Germany.
The establishment and maintenance of ion gradients between the interior of lysosomes and the cytosol are crucial for numerous cellular and organismal functions. Numerous ion transport proteins ensure the required variation in luminal concentrations of the different ions along the endocytic pathway to fit the needs of the organelles. Failures in keeping proper ion homeostasis have pathological consequences.
View Article and Find Full Text PDFCommon gating of both CLC transporter subunits underlies voltage-dependent activation of the 2Cl-/1H+ exchanger ClC-7/Ostm1.
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From the Leibniz-Institut für Molekulare Pharmakologie (FMP) and.
CLC anion transporters form dimers that function either as Cl(-) channels or as electrogenic Cl(-)/H(+) exchangers. CLC channels display two different types of "gates," "protopore" gates that open and close the two pores of a CLC dimer independently of each other and common gates that act on both pores simultaneously. ClC-7/Ostm1 is a lysosomal 2Cl(-)/1H(+) exchanger that is slowly activated by depolarization.
View Article and Find Full Text PDFClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity.
EMBO J
June 2011
Leibniz-Institut für Molekulare Pharmakologie (FMP) and Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.
Article Synopsis
- Mutations in the ClC-7/Ostm1 ion transporter cause osteopetrosis and lysosomal storage disease, and their lysosomal location has made functional studies difficult.
- Using a mutated version of ClC-7 that reaches the plasma membrane, researchers found that specific regions of the Ostm1 β-subunit are crucial for ClC-7's ion exchange function and its trafficking to lysosomes.
- The study revealed that the ion exchange occurs with a specific stoichiometry and identified how certain mutations can impact the ion exchange process, suggesting broader implications for the understanding of ion exchange mechanisms in cellular contexts.
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Pediatric Storage Disorders Laboratory, Department of Neuroscience, Centre for the Cellular Basis of Behavior, Institute of Psychiatry, King's College London, UK.
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