Structure of the human CLC-7/Ostm1 complex reveals a novel state

CLC-7 functions as a Cl⁻/H⁺ exchanger in lysosomes. Defects in CLC-7 and its β-subunit, Ostm1, result in osteopetrosis and neurodegeneration. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the human CLC-7/Ostm1 complex (HsCLC-7/Ostm1) at a resolution of 3.6 Å. Our structure reveals a new state of the CLC-7/Ostm1 heterotetramer, in which the cytoplasmic domain of CLC-7 is absent, likely due to high flexibility. The disordered cytoplasmic domain is probably not able to restrain CLC-7 subunits and thus allow their relative movements. The movements result in an approximately half smaller interface between the CLC-7 transmembrane domains than that in a previously reported CLC-7/Ostm1 structure with a well-folded cytoplasmic domain. Key interactions involving multiple osteopetrosis-related residues are affected by the interface change.