Scientific Report Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions
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چکیده
Loss of the lysosomal ClC-7/Ostm1 2Cl /H exchanger causes lysosomal storage disease and osteopetrosis in humans and additionally changes fur colour in mice. Its conversion into a Cl conductance in Clcn7 mice entails similarly severe lysosomal storage, but less severe osteopetrosis and no change in fur colour. To elucidate the basis for these phenotypical differences, we generated Clcn7 mice expressing an ion transport-deficient mutant. Their osteopetrosis was as severe as in Clcn7 / mice, suggesting that the electric shunt provided by ClC-7 can partially rescue osteoclast function. The normal coat colour of Clcn7 mice and their less severe neurodegeneration suggested that the ClC-7 protein, even when lacking measurable ion transport activity, is sufficient for hair pigmentation and that the conductance of ClC-7 is harmful for neurons. Our in vivo structure-function analysis of ClC-7 reveals that both proteinprotein interactions and ion transport must be considered in the pathogenesis of ClC-7-related diseases.
منابع مشابه
Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions.
Loss of the lysosomal ClC-7/Ostm1 2Cl(-)/H(+) exchanger causes lysosomal storage disease and osteopetrosis in humans and additionally changes fur colour in mice. Its conversion into a Cl(-) conductance in Clcn7(unc/unc) mice entails similarly severe lysosomal storage, but less severe osteopetrosis and no change in fur colour. To elucidate the basis for these phenotypical differences, we generat...
متن کاملLysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC-7.
Mutations in either ClC-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters, or in its beta-subunit Ostm1 cause osteopetrosis and lysosomal storage disease in mice and humans. The severe phenotype of mice globally deleted for ClC-7 or Ostm1 and the absence of storage material in cultured cells hampered investigations of the mechanism leading to lysosomal...
متن کاملClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity.
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 transmembra...
متن کاملA missense mutation accelerating the gating of the lysosomal Cl−/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle
Chloride-proton exchange by the lysosomal anion transporter ClC-7/Ostm1 is of pivotal importance for the physiology of lysosomes and bone resorption. Mice lacking either ClC-7 or Ostm1 develop a lysosomal storage disease and mutations in either protein have been found to underlie osteopetrosis in mice and humans. Some human disease-causing CLCN7 mutations accelerate the usually slow voltage-dep...
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