Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms
The vacuolar-type ATPase (V-ATPase) is a multisubunit protein composed of the cytosolic adenosine triphosphate (ATP) hydrolysis catalyzing V1 complex, and the integral membrane complex, Vo, responsible for proton translocation. The largest subunit of the Vo complex, subunit a, enables proton translo...
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1135015/full |
| _version_ | 1797789108841480192 |
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| author | Karen Indrawinata Peter Argiropoulos Shuzo Sugita Shuzo Sugita |
| author_facet | Karen Indrawinata Peter Argiropoulos Shuzo Sugita Shuzo Sugita |
| author_sort | Karen Indrawinata |
| collection | DOAJ |
| description | The vacuolar-type ATPase (V-ATPase) is a multisubunit protein composed of the cytosolic adenosine triphosphate (ATP) hydrolysis catalyzing V1 complex, and the integral membrane complex, Vo, responsible for proton translocation. The largest subunit of the Vo complex, subunit a, enables proton translocation upon ATP hydrolysis, mediated by the cytosolic V1 complex. Four known subunit a isoforms (a1–a4) are expressed in different cellular locations. Subunit a1 (also known as Voa1), the neural isoform, is strongly expressed in neurons and is encoded by the ATP6V0A1 gene. Global knockout of this gene in mice causes embryonic lethality, whereas pyramidal neuron-specific knockout resulted in neuronal cell death with impaired spatial and learning memory. Recently reported, de novo and biallelic mutations of the human ATP6V0A1 impair autophagic and lysosomal activities, contributing to neuronal cell death in developmental and epileptic encephalopathies (DEE) and early onset progressive myoclonus epilepsy (PME). The de novo heterozygous R740Q mutation is the most recurrent variant reported in cases of DEE. Homology studies suggest R740 deprotonates protons from specific glutamic acid residues in subunit c, highlighting its importance to the overall V-ATPase function. In this paper, we discuss the structure and mechanism of the V-ATPase, emphasizing how mutations in subunit a1 can lead to lysosomal and autophagic dysfunction in neurodevelopmental disorders, and how mutations to the non-neural isoforms, a2–a4, can also lead to various genetic diseases. Given the growing discovery of disease-causing variants of V-ATPase subunit a and its function as a pump-based regulator of intracellular organelle pH, this multiprotein complex warrants further investigation. |
| first_indexed | 2024-03-13T01:46:05Z |
| format | Article |
| id | doaj.art-d8c2814b83df48f3836d4ffa30ac1103 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-03-13T01:46:05Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-d8c2814b83df48f3836d4ffa30ac11032023-07-03T08:18:05ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-07-011610.3389/fnmol.2023.11350151135015Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoformsKaren Indrawinata0Peter Argiropoulos1Shuzo Sugita2Shuzo Sugita3Division of Translational and Experimental Neuroscience, Krembil Brain Institute, University Health Network, Toronto, ON, CanadaDivision of Translational and Experimental Neuroscience, Krembil Brain Institute, University Health Network, Toronto, ON, CanadaDivision of Translational and Experimental Neuroscience, Krembil Brain Institute, University Health Network, Toronto, ON, CanadaDepartment of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, CanadaThe vacuolar-type ATPase (V-ATPase) is a multisubunit protein composed of the cytosolic adenosine triphosphate (ATP) hydrolysis catalyzing V1 complex, and the integral membrane complex, Vo, responsible for proton translocation. The largest subunit of the Vo complex, subunit a, enables proton translocation upon ATP hydrolysis, mediated by the cytosolic V1 complex. Four known subunit a isoforms (a1–a4) are expressed in different cellular locations. Subunit a1 (also known as Voa1), the neural isoform, is strongly expressed in neurons and is encoded by the ATP6V0A1 gene. Global knockout of this gene in mice causes embryonic lethality, whereas pyramidal neuron-specific knockout resulted in neuronal cell death with impaired spatial and learning memory. Recently reported, de novo and biallelic mutations of the human ATP6V0A1 impair autophagic and lysosomal activities, contributing to neuronal cell death in developmental and epileptic encephalopathies (DEE) and early onset progressive myoclonus epilepsy (PME). The de novo heterozygous R740Q mutation is the most recurrent variant reported in cases of DEE. Homology studies suggest R740 deprotonates protons from specific glutamic acid residues in subunit c, highlighting its importance to the overall V-ATPase function. In this paper, we discuss the structure and mechanism of the V-ATPase, emphasizing how mutations in subunit a1 can lead to lysosomal and autophagic dysfunction in neurodevelopmental disorders, and how mutations to the non-neural isoforms, a2–a4, can also lead to various genetic diseases. Given the growing discovery of disease-causing variants of V-ATPase subunit a and its function as a pump-based regulator of intracellular organelle pH, this multiprotein complex warrants further investigation.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1135015/fullV-ATPasesubunit a1R740neurodevelopmental disordersdevelopmental and epileptic encephalopahtiesprogressive myoclonus epilepsy |
| spellingShingle | Karen Indrawinata Peter Argiropoulos Shuzo Sugita Shuzo Sugita Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms Frontiers in Molecular Neuroscience V-ATPase subunit a1 R740 neurodevelopmental disorders developmental and epileptic encephalopahties progressive myoclonus epilepsy |
| title | Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms |
| title_full | Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms |
| title_fullStr | Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms |
| title_full_unstemmed | Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms |
| title_short | Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms |
| title_sort | structural and functional understanding of disease associated mutations in v atpase subunit a1 and other isoforms |
| topic | V-ATPase subunit a1 R740 neurodevelopmental disorders developmental and epileptic encephalopahties progressive myoclonus epilepsy |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1135015/full |
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