Molecular Cell
Volume 75, Issue 5, 5 September 2019, Pages 1073-1085.e6
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Article
Unique Structural Features of the Mitochondrial AAA+ Protease AFG3L2 Reveal the Molecular Basis for Activity in Health and Disease

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Highlights

  • Substrate-bound structure of the mitochondrial AFG3L2 protease catalytic core

  • AFG3L2 evolved adaptations to promote a distinct mode of substrate handling

  • Specific structural features contact the substrate and stabilize the protease complex

  • Neurodegenerative disease mutations cluster to unique AFG3L2 structural elements

Summary

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

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