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Open AccessOpen Access JUSTC Article 06 April 2023

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

  • School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China

Cite this:
https://doi.org/10.52396/JUSTC-2022-0172
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  • Author Bio:

    Zhixuan Zhang is currently a master’s student under the supervision of Prof. Ji She at the University of Science and Technology of China. His research mainly focuses on the structure and function of membrane transporters

    Long Chen is currently a Ph.D. student under the supervision of Prof. Ji She at the University of Science and Technology of China. His research mainly focuses on the structure and function of membrane transporters

    Ji She is currently a Professor at the Division of Life Sciences and Medicine, University of Science and Technology of China. He received his Ph.D. degree in Physiology from Perking University. His research interests include ion transport mechanisms, the structure and function of transporters, and structure-based drug studies

  • Corresponding author: E-mail: jishe@ustc.edu.cn
  • Received Date: 28 November 2022
  • Accepted Date: 02 March 2023
    • Available Online: 06 April 2023
    Abstract

  • Abstract

    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.

    Graphical abstract

      A novel conformational state of CLC-7.

    Abstract

    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.

    • Public Summary

    • Structure of the human CLC-7/Ostm1 complex reveals a novel state with a disordered cytoplasmic domain.
    • The interface between the CLC-7 transmembrane domains is substantially reduced in the structure.
    • Key interactions involving multiple osteopetrosis-related residues are affected by the interface change.

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    • References(51)
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    Figure  1.  Overall structure of the HsCLC-7/Ostm1 complex. (a, b) 3D reconstruction (a) and cartoon representation (b) of the HsCLC-7/Ostm1 complex with each subunit in individual colors. (c) Topology of one HsCLC-7 subunit (orange) and one Ostm1 subunit (cyan). Dashed lines indicate flexible regions absent in the structure. (d) Comparison of the ion conduction pathways of HsCLC-7 and EcCLC.

    Figure  2.  Dimer interface of HsCLC-7. (a) Comparison of the transmembrane domains of the CLC-7 flexible (purple and orange) and CLC-7 stable (7JM7, cyan) structures (bottom view). Arrows indicate the shifts of helices. Linkers between helices are omitted for clarity. (b, c) Side view of the dimer interface of the CLC-7-stable (b) and CLC-7-flexible (c) structures. Residues on the interface are shown as sticks. (d, e) Bottom view (d) and side view (e) of the HsCLC-7-flexible structure with lipid density shown as blue mesh. (f) Cartoon representation of the CLC-stable structure. Ostm1 is not shown here. Blue bars indicate the interfaces between the cytoplasmic domain and the transmembrane domain, and the gray bar indicates the interface between the cytoplasmic domains. The cytoplasmic domain consists of CBS domains, the N-terminus, and an ATP molecule.

    Figure  3.  Disease-related residues on the dimer interface of HsCLC-7. (a, b) Detailed interaction changes between CLC-7-flexible (purple and orange) and CLC-7-stable (cyan). Key residues are shown as sticks. Lipids in (a) are omitted for clarity. (c) Working model of HsCLC-7 regulation by the cytoplasmic domain-mediated dimer change. The left panel shows the CLC-7 state with a well-folded cytoplasmic domain consisting of CBS domains, the N-terminus, and ATP. The right panel shows the CLC-7 state with disordered N-terminus and CBS domains.

    [1]
    Jentsch T J. Discovery of CLC transport proteins: Cloning, structure, function and pathophysiology. J. Physiol. , 2015, 593 (18): 4091–4109. doi: 10.1113/JP270043
    [2]
    Jentsch T J, Neagoe I, Scheel O. CLC chloride channels and transporters. Curr. Opin. Neurobiol. , 2005, 15 (3): 319–325. doi: 10.1016/j.conb.2005.05.002
    [3]
    Jentsch T J, Pusch M. CLC chloride channels and transporters: Structure, function, physiology, and disease. Physiol. Rev. , 2018, 98 (3): 1493–1590. doi: 10.1152/physrev.00047.2017
    [4]
    Steinmeyer K, Ortland C, Jentsch T J. Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel. Nature, 1991, 354: 301–304. doi: 10.1038/354301a0
    [5]
    Thiemann A, Gründer S, Pusch M, et al. A chloride channel widely expressed in epithelial and non-epithelial cells. Nature, 1992, 356: 57–60. doi: 10.1038/356057a0
    [6]
    Kieferle S, Fong P, Bens M, et al. Two highly homologous members of the ClC chloride channel family in both rat and human kidney. Proc. Natl. Acad. Sci. U. S. A. , 1994, 91 (15): 6943–6947. doi: 10.1073/pnas.91.15.6943
    [7]
    Leisle L, Ludwig C F, Wagner F A, et al. ClC-7 is a slowly voltage-gated 2Cl−/1H+-exchanger and requires Ostm1 for transport activity. EMBO J., 2011, 30 (11): 2140–2152. doi: 10.1038/emboj.2011.137
    [8]
    Scheel O, Zdebik A A, Lourdel S, et al. Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature, 2005, 436: 424–427. doi: 10.1038/nature03860
    [9]
    Neagoe I, Stauber T, Fidzinski P, et al. The late endosomal ClC-6 mediates proton/chloride countertransport in heterologous plasma membrane expression. J. Biol. Chem. , 2010, 285 (28): 21689–21697. doi: 10.1074/jbc.M110.125971
    [10]
    Picollo A, Pusch M. Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature, 2005, 436: 420–423. doi: 10.1038/nature03720
    [11]
    Kornak U, Kasper D, Bösl M R, et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell, 2001, 104 (2): 205–215. doi: 10.1016/S0092-8674(01)00206-9
    [12]
    Kasper D, Planells-Cases R, Fuhrmann J C, et al. Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. EMBO J., 2005, 24 (5): 1079–1091. doi: 10.1038/sj.emboj.7600576
    [13]
    Sobacchi C, Schulz A, Coxon F P, et al. Osteopetrosis: Genetics, treatment and new insights into osteoclast function. Nat. Rev. Endocrinol., 2013, 9 (9): 522–536. doi: 10.1038/nrendo.2013.137
    [14]
    Weinert S, Jabs S, Supanchart C, et al. Lysosomal pathology and osteopetrosis upon loss of H+-driven lysosomal Cl- accumulation. Science, 2010, 328: 1401–1403. doi: 10.1126/science.1188072
    [15]
    Zifarelli G. The role of the lysosomal Cl−/H+antiporter ClC-7 in osteopetrosis and neurodegeneration. Cells, 2022, 11 (3): 366. doi: 10.3390/cells11030366
    [16]
    Pressey S N R, O'Donnell K J, Stauber T, et al. Distinct neuropathologic phenotypes after disrupting the chloride transport proteins ClC-6 or ClC-7/Ostm1. J. Neuropathol. Exp. Neurol., 2010, 69 (12): 1228–1246. doi: 10.1097/NEN.0b013e3181ffe742
    [17]
    Lange P F, Wartosch L, Jentsch T J, et al. ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature, 2006, 440: 220–223. doi: 10.1038/nature04535
    [18]
    Pangrazio A, Poliani P L, Megarbane A, et al. Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement. J. Bone Miner. Res. , 2006, 21 (7): 1098–1105. doi: 10.1359/jbmr.060403
    [19]
    Castellano Chiodo D, DiRocco M, Gandolfo C, et al. Neuroimaging findings in malignant infantile osteopetrosis due to OSTM1 mutations. Neuropediatrics, 2007, 38 (3): 154–156. doi: 10.1055/s-2007-990267
    [20]
    Dutzler R, Campbell E B, Cadene M, et al. X-ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity. Nature, 2002, 415: 287–294. doi: 10.1038/415287a
    [21]
    Park E, Campbell E B, MacKinnon R. Structure of a CLC chloride ion channel by cryo-electron microscopy. Nature, 2017, 541: 500–505. doi: 10.1038/nature20812
    [22]
    Park E, MacKinnon R. Structure of the CLC-1 chloride channel from Homo sapiens. eLife, 2018, 7: e36629. doi: 10.7554/eLife.36629
    [23]
    Feng L, Campbell E B, Hsiung Y, et al. Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle. Science, 2010, 330: 635–641. doi: 10.1126/science.1195230
    [24]
    Dutzler R, Campbell E B, MacKinnon R. Gating the selectivity filter in ClC chloride channels. Science, 2003, 300: 108–112. doi: 10.1126/science.1082708
    [25]
    Feng L, Campbell E B, MacKinnon R. Molecular mechanism of proton transport in CLC Cl−/H+ exchange transporters. Proc. Natl. Acad. Sci. U. S. A., 2012, 109 (29): 11699–11704. doi: 10.1073/pnas.1205764109
    [26]
    Schrecker M, Korobenko J, Hite R K. Cryo-EM structure of the lysosomal chloride-proton exchanger CLC-7 in complex with OSTM1. eLife, 2020, 9: e59555. doi: 10.7554/eLife.59555
    [27]
    Zhang S, Liu Y, Zhang B, et al. Molecular insights into the human CLC-7/Ostm1 transporter. Sci. Adv., 2020, 6 (33): eabb4747. doi: 10.1126/sciadv.abb4747
    [28]
    Accardi A, Walden M, Nguitragool W, et al. Separate ion pathways in a Cl−/H+ exchanger. J. Gen. Physiol., 2005, 126 (6): 563–570. doi: 10.1085/jgp.200509417
    [29]
    Morales-Perez C L, Noviello C M, Hibbs R E. Manipulation of subunit stoichiometry in heteromeric membrane proteins. Structure, 2016, 24 (5): 797–805. doi: 10.1016/j.str.2016.03.004
    [30]
    She J, Zeng W, Guo J, et al. Structural mechanisms of phospholipid activation of the human TPC2 channel. eLife, 2019, 8: e45222. doi: 10.7554/eLife.45222
    [31]
    Zheng S Q, Palovcak E, Armache J P, et al. MotionCor2: Anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods, 2017, 14 (4): 331–332. doi: 10.1038/nmeth.4193
    [32]
    Zhang K. Gctf: Real-time CTF determination and correction. J. Struct. Biol., 2016, 193 (1): 1–12. doi: 10.1016/j.jsb.2015.11.003
    [33]
    Kimanius D, Forsberg B O, Scheres S H, et al. Accelerated cryo-EM structure determination with parallelisation using GPUs in RELION-2. eLife, 2016, 5: e18722. doi: 10.7554/eLife.18722
    [34]
    Kucukelbir A, Sigworth F J, Tagare H D. Quantifying the local resolution of cryo-EM density maps. Nat. Methods, 2014, 11 (1): 63–65. doi: 10.1038/nmeth.2727
    [35]
    Emsley P, Lohkamp B, Scott W G, et al. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr., 2010, 66: 486–501. doi: 10.1107/S0907444910007493
    [36]
    Terwilliger T C, Adams P D, Afonine P V, et al. A fully automatic method yielding initial models from high-resolution cryo-electron microscopy maps. Nat. Methods, 2018, 15 (11): 905–908. doi: 10.1038/s41592-018-0173-1
    [37]
    Afonine P V, Poon B K, Read R J, et al. Real-space refinement in PHENIX for cryo-EM and crystallography. Acta Crystallogr. D Struct. Biol., 2018, 74: 531–544. doi: 10.1107/S2059798318006551
    [38]
    Afonine P V, Klaholz B P, Moriarty N W, et al. New tools for the analysis and validation of cryo-EM maps and atomic models. Acta Crystallogr. D Struct. Biol., 2018, 74: 814–840. doi: 10.1107/S2059798318009324
    [39]
    Chen V B, Arendall III W B, Headd J J, et al. MolProbity: All-atom structure validation for macromolecular crystallography. Acta Crystallographica Section D, 2020, 66: 12–21. doi: 10.1107/S0907444909042073
    [40]
    Pettersen E F, Goddard T D, Huang C C, et al. UCSF Chimera: A visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25 (13): 1605–1612. doi: 10.1002/jcc.20084
    [41]
    Goddard T D, Huang C C, Meng E C, et al. UCSF ChimeraX: Meeting modern challenges in visualization and analysis. Protein Sci., 2018, 27 (1): 14–25. doi: 10.1002/pro.3235
    [42]
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