Unique Structural Features of the Mitochondrial AAA+ Protease AFG3L2 Reveal the Molecular Basis for Activity in Health and Disease
- Mol Cell. 2019 Sep 5;75(5):1073-1085.e6. doi: 10.1016/j.molcel.2019.06.016.
- 1. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
- 2. Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA.
- 3. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
- 4. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: [email protected].
- 5. Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: [email protected].
Mitochondrial AAA+ quality-control proteases regulate diverse aspects of mitochondrial biology through specialized protein degradation, but the underlying mechanisms of these Enzymes remain poorly defined. The mitochondrial AAA+ protease AFG3L2 is of particular interest, as genetic mutations localized throughout AFG3L2 are linked to diverse neurodegenerative disorders. However, a lack of structural data has limited our understanding of how mutations impact enzymatic function. Here, we used cryoelectron microscopy (cryo-EM) to determine a substrate-bound structure of the catalytic core of human AFG3L2. This structure identifies multiple specialized structural features that integrate with conserved motifs required for ATP-dependent translocation to unfold and degrade targeted proteins. Many disease-relevant mutations localize to these unique structural features of AFG3L2 and distinctly influence its activity and stability. Our results provide a molecular basis for neurological phenotypes associated with different AFG3L2 mutations and establish a structural framework to understand how different members of the AAA+ superfamily achieve specialized biological functions.