Abstract
OPA1 is a dynamin-related GTPase that controls mitochondrial fusion, cristae remodeling, energetics and mtDNA maintenance. However, the molecular architecture of OPA1 is poorly understood. Here we modeled the structure of human OPA1 by the threading approach. We found that the C-terminal region of the OPA1 protein had multiple functional domains, while the N-terminal region was rich in alpha helices and did not include specific domains. For the short soluble forms of OPA1, we observed that there were obvious hydrophobic regions near the two cleavage sites and the N-terminal was positively charged after cleavage. The blue native analysis revealed that the protein could form stable homodimers. In addition, the evolutionary conservation of the C-terminal region, where most of the known mutated disease-related sites were located, was significantly higher than that of the N-terminal region. These findings provided new insights into the structure and biochemical function of OPA1.
Highlights
Mitochondria undergo a constant dynamic balance between organelles fusion and fission to maintain their network morphology and functions (Van der Bliek, Shen & Kawajiri, 2013; Wai & Langer, 2016)
The GTPase domains of the two monomers were approximately 100 Å apart, and the dimeric interaction interface involved in 33 pairs of interaction among 18 amino acid sites, 17 pairs of which were from the interaction between two middle domains, 12 pairs of which were from the interaction between the middle domain and the GTPase effector domain (GED), and four pairs from the interaction between the two GED domains (Fig. 4B). These results indicated that, similar to dynamin 1 and MxA, optic atrophy 1 (OPA1) could assemble to dimers and higher-order oligomers via middle domain and GED, which was different from mitofusins that mediated membrane fusion by GTPase domains (Cao et al, 2017)
We modeled the whole structure of human OPA1 protein, revealing that its structure was divided into N-terminal and C-terminal region
Summary
Mitochondria undergo a constant dynamic balance between organelles fusion and fission to maintain their network morphology and functions (Van der Bliek, Shen & Kawajiri, 2013; Wai & Langer, 2016). Several conserved GTPase mediate the mitochondrial dynamics: mitofusins (mitofusin 1 and mitofusin 2) control fusion of the outer mitochondrial membrane (OMM) while Drp is involved in fission of OMM (Labbe, Murley & Nunnari, 2014; Pernas & Scorrano, 2016); the conserved dynamin-related GTPase optic atrophy 1 (OPA1) is indispensable for both cristae morphology and the inner mitochondrial membrane (IMM) fusion (Belenguer & Pellegrini, 2013; Del Dotto et al, 2018a; Pernas & Scorrano, 2016). Structural and evolutionary characteristics of dynamin-related GTPase OPA1.
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