The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index.
Disruption of CAD Oligomerization by Pathogenic Variants
Open accessPublished version of a preprint
Abstract
ABSTRACT CAD is a multi-enzymatic protein essential for initiating the de novo biosynthesis of pyrimidine nucleotides, forming large hexamers whose structure and function are not fully understood. Defects in CAD result in a severe neurometabolic disorder that is challenging to diagnose. We developed a cellular functional assay to identify defective CAD variants, and in this study, we characterized five pathogenic missense mutations in CAD’s dihydroorotase (DHO) and aspartate transcarbamylase (ATC) domains. All mutations impaired enzymatic activities, with two notably disrupting the formation of DHO dimers and ATC trimers. Combining crystal structures and AlphaFold predictions, we modeled the hexameric CAD complex, highlighting the central role of the DHO and ATC domains in its assembly. Our findings provide insight into CAD’s stability, function, and organization, revealing that correct oligomerization of CAD into a supramolecular complex is required for its function in nucleotide synthesis and that mutations affecting this assembly are potentially pathogenic.
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Metadata
- Authors
- Del Caño-Ochoa, F., Ramadane-Morchadi, L., Eixerés, L., Moreno-Morcillo, M., Fernández-Leiro, R., & Ramón-Maiques, S.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Spanish National Cancer Research Centre (ES)
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 436
- Issue
- 23
- Pages
- 168832
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W4403628001
- Cited by
- 2
- References
- 69
- Citations by year
- 2025: 2
- FWCI
- 0.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
- Locations
- Journal of Molecular Biology (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
- Funders
- Ramon Areces Foundation
- Spain Ministry of Science and Innovation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- 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
- Keywords
- protein trimerization, protein dimerization, pyrimidine synthesis, neurometabolic disorders
- MeSH terms
- Protein Domains, Aspartate Carbamoyltransferase, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Dihydroorotase, Humans, Models, Molecular, Pentosyltransferases, Protein Conformation, Crystallography, X-Ray, Mutation, Missense, Protein Multimerization
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- Del Caño-Ochoa, F., Ramadane-Morchadi, L., Eixerés, L., Moreno-Morcillo, M., Fernández-Leiro, R., & Ramón-Maiques, S. (2024). Disruption of CAD Oligomerization by Pathogenic Variants. Journal of Molecular Biology. https://doi.org/10.1016/j.jmb.2024.168832
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
