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Mol Cell. 2019 Sep 5;75(5):1073-1085.e6. doi: 10.1016/j.molcel.2019.06.016. Epub 2019 Jul 18.

Unique Structural Features of the Mitochondrial AAA+ Protease AFG3L2 Reveal the Molecular Basis for Activity in Health and Disease.

Author information

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: glander@scripps.edu.
5
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: steven.glynn@stonybrook.edu.

Abstract

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.

KEYWORDS:

AAA+ protease; mitochondrial quality control; neurodegenerative disease; spinocerebellar ataxia type 28

PMID:
31327635
PMCID:
PMC6731152
[Available on 2020-09-05]
DOI:
10.1016/j.molcel.2019.06.016

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