8ef7
From Proteopedia
CryoEM of the soluble OPA1 dimer from the apo helical assembly on a lipid membrane
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 PubMedDominant optic atrophy is one of the leading causes of childhood blindness. Around 60-80% of cases(1) are caused by mutations of the gene that encodes optic atrophy protein 1 (OPA1), a protein that has a key role in inner mitochondrial membrane fusion and remodelling of cristae and is crucial for the dynamic organization and regulation of mitochondria(2). Mutations in OPA1 result in the dysregulation of the GTPase-mediated fusion process of the mitochondrial inner and outer membranes(3). Here we used cryo-electron microscopy methods to solve helical structures of OPA1 assembled on lipid membrane tubes, in the presence and absence of nucleotide. These helical assemblies organize into densely packed protein rungs with minimal inter-rung connectivity, and exhibit nucleotide-dependent dimerization of the GTPase domains-a hallmark of the dynamin superfamily of proteins(4). OPA1 also contains several unique secondary structures in the paddle domain that strengthen its membrane association, including membrane-inserting helices. The structural features identified in this study shed light on the effects of pathogenic point mutations on protein folding, inter-protein assembly and membrane interactions. Furthermore, mutations that disrupt the assembly interfaces and membrane binding of OPA1 cause mitochondrial fragmentation in cell-based assays, providing evidence of the biological relevance of these interactions. OPA1 helical structures give perspective to mitochondrial dysfunction.,Nyenhuis SB, Wu X, Strub MP, Yim YI, Stanton AE, Baena V, Syed ZA, Canagarajah B, Hammer JA, Hinshaw JE Nature. 2023 Aug;620(7976):1109-1116. doi: 10.1038/s41586-023-06462-1. Epub 2023 , Aug 23. PMID:37612506[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Canagarajah B | Hinshaw JE | Nyenhuis SB | Stanton AE | Strub MP | Wu X | Yim YI
