Journal Article

OPA1 helical structures give perspective to mitochondrial dysfunction

Nyenhuis, Sarah B., Strub, Marie-Paule, Baena, Valentina, Stanton, Abigail E., Wu, Xufeng, Syed, Zulfeqhar A., Hinshaw, Jenny E., Canagarajah, Bertram, Yim, Yang-In, Hammer, John A.

2023

Overview

Dominant 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. Cryo-electron microscopy structures of OPA1, mutations of which are associated with the disease dominant optic atrophy, provide insight into how structural features of OPA1 enable this protein to mediate mitochondrial-membrane fusion and remodelling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 14/19 / 631/535/1258/1259 / 631/80/642/333 / 82/83 / Assembly / Atrophy / Children / Cristae / Cryoelectron Microscopy / Dimerization / Dynamin / Electron microscopy / GTP Phosphohydrolases - chemistry / GTP Phosphohydrolases - genetics / GTP Phosphohydrolases - metabolism / GTP Phosphohydrolases - ultrastructure / Helices / Humanities and Social Sciences / Humans / Interfaces / Lipids / Membrane Fusion / Membrane proteins / Membranes / Microscopy / Mitochondria / Mitochondria - enzymology / Mitochondria - metabolism / Mitochondria - pathology / Mitochondrial DNA / Mitochondrial Dynamics / Mitochondrial Membranes - metabolism / multidisciplinary / Mutation / Nucleotides / Nucleotides - metabolism / Optic atrophy / Protein Binding - genetics / Protein Domains / Protein Folding / Protein Multimerization / Protein Structure, Secondary / Proteins / Science / Science (multidisciplinary) / Tubes