ArticleBiochemistry2018
Dissecting Substrate Specificities of the Mitochondrial AFG3L2 Protease.
Article in Biochemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 23 citations in OpenAlex.
- Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.CNS neuroscience & therapeutics · 2026Article
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- Physalin F Promotes AFG3L2-Mediated Degradation of VISA/MAVS to Suppress Innate Immune Response to RNA Virus.Pathogens (Basel, Switzerland) · 2026Article
- SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis.Molecular cell · 2025Article
- Substrate-dependent activation of LONP1 informs on proteolytic regulation and ATPase motor function.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Maintaining the Integral Membrane Proteome: Revisiting the Functional Repertoire of Integral Membrane Proteases.Chembiochem : a European journal of chemical biology · 2025Review
- Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders.Molecular neurobiology · 2024Review
- Structural and mechanistic studies on human LONP1 redefine the hand-over-hand translocation mechanism.bioRxiv : the preprint server for biology · 2024Article
- Novel compound heterozygous mutations in theHeliyon · 2023Article
- A novel mutation located in the intermembrane space domain of AFG3L2 causes dominant optic atrophy through decreasing the stability of the encoded protein.Cell death discovery · 2022Article
- Review
- Mitochondrial AAA proteases: A stairway to degradation.Mitochondrion · 2019Review
- Unique Structural Features of the Mitochondrial AAA+ Protease AFG3L2 Reveal the Molecular Basis for Activity in Health and Disease.Molecular cell · 2019Article
- Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Human AFG3L2 is a compartmental AAA+ protease that performs ATP-fueled degradation at the matrix face of the inner mitochondrial membrane. Identifying how AFG3L2 selects substrates from the diverse complement of matrix-localized proteins is essential for understanding mitochondrial protein biogenesis and quality control. Here, we create solubilized forms of AFG3L2 to examine the enzyme's substrate specificity mechanisms. We show that conserved residues within the presequence of the mitochondrial ribosomal protein, MrpL32, target the subunit to the protease for processing into a mature form. Moreover, these residues can act as a degron, delivering diverse model proteins to AFG3L2 for degradation. By determining the sequence of degradation products from multiple substrates using mass spectrometry, we construct a peptidase specificity profile that displays constrained product lengths and is dominated by the identity of the residue at the P1' position, with a strong preference for hydrophobic and small polar residues. This specificity profile is validated by examining the cleavage of both fluorogenic reporter peptides and full polypeptide substrates bearing different P1' residues. Together, these results demonstrate that AFG3L2 contains multiple modes of specificity, discriminating between potential substrates by recognizing accessible degron sequences and performing peptide bond cleavage at preferred patterns of residues within the compartmental chamber.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.