Defective nucleotide-dependent assembly and membrane fusion in Mfn2 CMT2A variants improved by Bax
© 2020 Samanas et al..
Mitofusins are members of the dynamin-related protein family of large GTPases that harness the energy from nucleotide hydrolysis to remodel membranes. Mitofusins possess four structural domains, including a GTPase domain, two extended helical bundles (HB1 and HB2), and a transmembrane region. We have characterized four Charcot-Marie-Tooth type 2A-associated variants with amino acid substitutions in Mfn2 that are proximal to the hinge that connects HB1 and HB2. A functional defect was not apparent in cells as the mitochondrial morphology of Mfn2-null cells was restored by expression of any of these variants. However, a significant fusion deficiency was observed in vitro, which was improved by the addition of crude cytosol extract or soluble Bax. All four variants had reduced nucleotide-dependent assembly in cis, but not trans, and this was also improved by the addition of Bax. Together, our data demonstrate an important role for this region in Mfn2 GTP-dependent oligomerization and membrane fusion and is consistent with a model where cytosolic factors such as Bax are masking molecular defects associated with Mfn2 disease variants in cells.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:3 |
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| Enthalten in: |
Life science alliance - 3(2020), 5 vom: 02. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Samanas, Nyssa B [VerfasserIn] |
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| Links: |
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| Themen: |
BAX protein, human |
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| Anmerkungen: |
Date Completed 02.06.2021 Date Revised 30.11.2021 published: Electronic-Print PDB: 2W6D, 2J69, 6JFK Citation Status MEDLINE |
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| doi: |
10.26508/lsa.201900527 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308312635 |
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| 245 | 1 | 0 | |a Defective nucleotide-dependent assembly and membrane fusion in Mfn2 CMT2A variants improved by Bax |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 Samanas et al. | ||
| 520 | |a Mitofusins are members of the dynamin-related protein family of large GTPases that harness the energy from nucleotide hydrolysis to remodel membranes. Mitofusins possess four structural domains, including a GTPase domain, two extended helical bundles (HB1 and HB2), and a transmembrane region. We have characterized four Charcot-Marie-Tooth type 2A-associated variants with amino acid substitutions in Mfn2 that are proximal to the hinge that connects HB1 and HB2. A functional defect was not apparent in cells as the mitochondrial morphology of Mfn2-null cells was restored by expression of any of these variants. However, a significant fusion deficiency was observed in vitro, which was improved by the addition of crude cytosol extract or soluble Bax. All four variants had reduced nucleotide-dependent assembly in cis, but not trans, and this was also improved by the addition of Bax. Together, our data demonstrate an important role for this region in Mfn2 GTP-dependent oligomerization and membrane fusion and is consistent with a model where cytosolic factors such as Bax are masking molecular defects associated with Mfn2 disease variants in cells | ||
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