ArticleProceedings of the National Academy of Sciences of the United States of America2020
Structure of the human clamp loader reveals an autoinhibited conformation of a substrate-bound AAA+ switch.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 60 citations in OpenAlex.
- Mechanistic diversity of clamp loading at small DNA gaps.The Journal of biological chemistry · 2026Review
- Biophysical insights into a cryptic ligand site in the hydrophobic core of human PCNA.Biophysical journal · 2026Article
- The E. coli DnaX clamp loader sharply bends DNA to load β-clamp at nicks and small gaps.Molecular cell · 2026Article
- Article
- ThebioRxiv : the preprint server for biology · 2026Article
- SHPRH together with the Ube2D family of enzymes directly ubiquitinates PCNA at Lys164 in vitro.PloS one · 2026Article
- Serial innovations by Asgard archaea shaped the DNA replication machinery of the early eukaryotic ancestor.Nature ecology & evolution · 2025Article
- PCNA is a nucleotide exchange factor for the clamp loader ATPase complex.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structure of the human CTF18-RFC clamp loader bound to PCNA.bioRxiv : the preprint server for biology · 2025Article
- Effects of Chemical Cross-Linking on the Structure of Proteins and Protein Assemblies.Analytical chemistry · 2025Article
- PCNA is a Nucleotide Exchange Factor for the Clamp Loader ATPase Complex.bioRxiv : the preprint server for biology · 2025Article
- Disruption of the moonlighting function of CTF18 in a patient with T-lymphopenia.Frontiers in immunology · 2025Article
- The human ATAD5 has evolved unique structural elements to function exclusively as a PCNA unloader.Nature structural & molecular biology · 2024Article
- Structural characterisation of the complete cycle of sliding clamp loading in Escherichia coli.Nature communications · 2024Article
- Expanding the genetic and phenotypic landscape of replication factor C complex-related disorders: RFC4 deficiency is linked to a multisystemic disorder.American journal of human genetics · 2024Article
- Mechanism of PCNA loading by Ctf18-RFC for leading-strand DNA synthesis.Science (New York, N.Y.) · 2024Article
- Cryo-EM reveals a nearly complete PCNA loading process and unique features of the human alternative clamp loader CTF18-RFC.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Differences between bacteria and eukaryotes in clamp loader mechanism, a conserved process underlying DNA replication.The Journal of biological chemistry · 2024Article
- Structure of the PCNA unloader Elg1-RFC.Science advances · 2024Article
- Differences in clamp loader mechanism between bacteria and eukaryotes.bioRxiv : the preprint server for biology · 2023Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
DNA replication requires the sliding clamp, a ring-shaped protein complex that encircles DNA, where it acts as an essential cofactor for DNA polymerases and other proteins. The sliding clamp needs to be opened and installed onto DNA by a clamp loader ATPase of the AAA+ family. The human clamp loader replication factor C (RFC) and sliding clamp proliferating cell nuclear antigen (PCNA) are both essential and play critical roles in several diseases. Despite decades of study, no structure of human RFC has been resolved. Here, we report the structure of human RFC bound to PCNA by cryogenic electron microscopy to an overall resolution of ∼3.4 Å. The active sites of RFC are fully bound to adenosine 5'-triphosphate (ATP) analogs, which is expected to induce opening of the sliding clamp. However, we observe the complex in a conformation before PCNA opening, with the clamp loader ATPase modules forming an overtwisted spiral that is incapable of binding DNA or hydrolyzing ATP. The autoinhibited conformation observed here has many similarities to a previous yeast RFC:PCNA crystal structure, suggesting that eukaryotic clamp loaders adopt a similar autoinhibited state early on in clamp loading. Our results point to a "limited change/induced fit" mechanism in which the clamp first opens, followed by DNA binding, inducing opening of the loader to release autoinhibition. The proposed change from an overtwisted to an active conformation reveals an additional regulatory mechanism for AAA+ ATPases. Finally, our structural analysis of disease mutations leads to a mechanistic explanation for the role of RFC in human health.
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