8ct1
CryoEM structure of human S-OPA1 assembled on lipid membrane in membrane-adjacent state
Structural highlights
DiseaseOPA1_HUMAN Autosomal dominant optic atrophy, classic form;Autosomal dominant optic atrophy plus syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionOPA1_HUMAN Dynamin-related GTPase that is essential for normal mitochondrial morphology by regulating the equilibrium between mitochondrial fusion and mitochondrial fission (PubMed:16778770, PubMed:17709429, PubMed:20185555, PubMed:24616225, PubMed:28746876). Coexpression of isoform 1 with shorter alternative products is required for optimal activity in promoting mitochondrial fusion (PubMed:17709429). Binds lipid membranes enriched in negatively charged phospholipids, such as cardiolipin, and promotes membrane tubulation (PubMed:20185555). The intrinsic GTPase activity is low, and is strongly increased by interaction with lipid membranes (PubMed:20185555). Plays a role in remodeling cristae and the release of cytochrome c during apoptosis (By similarity). Proteolytic processing in response to intrinsic apoptotic signals may lead to disassembly of OPA1 oligomers and release of the caspase activator cytochrome C (CYCS) into the mitochondrial intermembrane space (By similarity). Plays a role in mitochondrial genome maintenance (PubMed:20974897, PubMed:18158317).[UniProtKB:P58281][1] [2] [3] [4] [5] [6] [7] Inactive form produced by cleavage at S1 position by OMA1 following stress conditions that induce loss of mitochondrial membrane potential, leading to negative regulation of mitochondrial fusion.[8] Isoforms that contain the alternative exon 4b (present in isoform 4 and isoform 5) are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane.[9] Publication Abstract from PubMedDistinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate(1-3). The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane(4,5). Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions. Structural mechanism of mitochondrial membrane remodelling by human OPA1.,von der Malsburg A, Sapp GM, Zuccaro KE, von Appen A, Moss FR 3rd, Kalia R, Bennett JA, Abriata LA, Dal Peraro M, van der Laan M, Frost A, Aydin H Nature. 2023 Aug;620(7976):1101-1108. doi: 10.1038/s41586-023-06441-6. Epub 2023 , Aug 23. PMID:37612504[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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