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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.
Pubmed ID: 31327635
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A Python-based software suite for the automated determination of molecular structures using X-ray crystallography and other methods. Phenix includes programs for assessing data quality, experimental phasing, molecular replacement, model building, structure refinement, and validation. It also includes tools for reflection data and creating maps and models. Phenix can also be used for neutron crystallography. Tutorials and examples are available in the documentation tab.
View all literature mentionsSystem designed for automated collection of images from a transmission electron microscope.
View all literature mentionsSoftware tool for finding CTFs of electron micrographs. Program used for the estimation of objective lens defocus parameters from transmission electron micrographs. The program CTFFIND3 is an updated version of the program CTFFIND2. For micrographs collected on photographic film and scanned in use CTFFIND 3. For images from CCDs or direct detectors use CTFFIND 4.
View all literature mentionsSoftware package for processing and analysis of EM images. Appion is integrated with Leginon data acquisition but can also be used stand-alone after uploading images (either digital or scanned micrographs) or particle stacks using a set of provided tools.
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets alpha-Tubulin antibody produced in mouse
View all literature mentionsThis polyclonal targets AFG3L2
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