Opa1 helical structures give perspective to mitochondrial dysfunction
Research Square (Research Square)(2022)
Abstract
Abstract Dominant Optic Atrophy is the leading cause of childhood blindness, with 60-80% of cases caused by mutation of the gene encoding the protein Optic Atrophy 1, OPA1. This condition dysregulates the GTPase mediated fusion process of the mitochondrial inner- and outer-membranes. OPA1 is critical to the dynamic organization and regulation of the mitochondria due to its role in cristae remodeling and GTPase-mediated fusion of the inner mitochondrial membrane. Here, we solved helical structures of OPA1 assembled on lipid membrane tubes, in the presence and absence of nucleotide by cryo-electron microscopy methods. 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 dynamin superfamily proteins (DSPs). In contrast to other DSPs, OPA1 contains several unique secondary structures in the paddle domain that strengthen its membrane association. The novel structural features identified in this study shed light on the effects of pathogenic point mutations on protein folding, inter-protein assembly, and membrane interactions. Further, mutations chosen to disrupt OPA1 assembly interfaces and membrane binding cause mitochondrial fragmentation in cell-based assays, demonstrating the biological relevance of these interactions.
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Key words
helical structures
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