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Discovery, Structure, and Function of Filamentous 3-Methylcrotonyl-CoA Carboxylase
Open accessPreprint — published as 10.1016/j.str.2022.11.015 · Paper page
Abstract
SUMMARY: 3-methylcrotonyl-CoA carboxylase (MCC) is a biotin-dependent enzyme necessary for leucine catabolism in most organisms. While the crystal structure of recombinant bacterial MCC has been characterized, the structure and potential polymerization of native MCC remain elusive. Here, we discovered that native MCC from Leishmania tarentolae (LtMCC) forms filaments and determined its structure at near-atomic resolution using cryoEM. α 6 β 6 LtMCC dodecamers assemble in a twisted-stacks architecture, manifesting as supramolecular rods extending up to approximately 400 nanometers. LtMCCs in filaments bind biotin but are not covalently biotinylated and lack coenzyme A. Filaments elongate by stacking α 6 β 6 LtMCCs onto the exterior α-trimer of the terminal α 6 β 6 dodecamer. This stacking immobilizes the biotin carboxylase domains, sequestering the enzyme in an inactive state within the mitochondrial matrix. Our results support a new model for LtMCC catalysis, termed the dual-swinging-domains model, and cast new light on the functional significance of polymerization in the carboxylase superfamily and beyond.
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Metadata
- Authors
- Hu, J. J., Lee, J. K. J., Liu, Y.-T., Yu, C., Huang, L., Aphasizheva, I., Aphasizhev, R., & Zhou, Z. H.
- Affiliations
- California NanoSystems Institute (US)
- University of California, Irvine (US)
- Boston University (US)
- Corresponding author
- Zhou, Z. Hong
- ORCID
- Venue
- Structure
- Publisher
- openRxiv
- Published
- 2022-08-20
- Volume
- 31
- Issue
- 1
- Pages
- 100-110.e4
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC9825669
- OpenAlex
- W4312082529
- Cited by
- 29
- References
- 1
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 16 · 2023: 4
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Structure (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation (DBI-133813, 1548924)
- National Institutes of Health (1s10od018111-01)
- University of California, Los Angeles
- National Institute of General Medical Sciences (R01GM074830, R01GM071940)
- National Institute of Allergy and Infectious Diseases (R01AI113157, R01AI152408, R01AI101057)
- Division of Materials Research (DMR1548924, 1548924)
- National Center for Research Resources (S10RR023057)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
- Keywords
- 3-methylcrotonyl-CoA carboxylase, Leishmania tarentolae, supramolecular self-assembly, biotin binding, leucine catabolism, enzyme mechanism, mitochondrial enzymes
- MeSH terms
- Acyl Coenzyme A, Biotin, Carboxy-Lyases, Coenzyme A
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