ArticleProceedings of the National Academy of Sciences of the United States of America2022
Shelterin is a dimeric complex with extensive structural heterogeneity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 44 citations in OpenAlex.
- CDK2-mediated phosphorylation of TRF1 S11 facilitates DNA damage repair by remodeling telomeric chromatin.Cell death and differentiation · 2026Article
- Inhibition of lagging strand replication by G-rich telomeric DNA and the shelterin subunit POT1.The EMBO journal · 2026Article
- Telomere-associated non-malignant pulmonary diseases: Pathogenic mechanisms and therapeutic strategies.Acta pharmaceutica Sinica. B · 2026Review
- Best practice mass photometry: a guide to optimal single-molecule mass measurement.Nature protocols · 2026Review
- Mathematical modelling of premature haematopoietic ageing in dyskeratosis congenita.Scientific reports · 2026Article
- Structural basis for TRF2-RAP1 recruitment by EBNA1 at the EBV origin of replication.Scientific reports · 2026Article
- Deep Learning-Based Event Classification of Mass Photometry Data for Optimal Mass Measurement at the Single-Molecule Level.ACS nano · 2026Article
- Structural organization and function of telomeric chromatin.Nature cell biology · 2026Review
- High TERF2 expression is associated with poor prognosis and its suppression attenuates progression in acute myeloid leukemia.Translational cancer research · 2025Article
- Discovery of first-in-class inhibitors of the TRF1:TIN2 protein:protein interaction by fragment screening.Scientific reports · 2025Article
- Potential dietary geroprotectors and their impact on key mechanisms of aging.Biogerontology · 2025Review
- Structural Basis for TRF2-RAP1 Recruitment by EBNA1 at the EBV origin of replication.Research square · 2025Article
- Telomere-Related Gene Networks in the Ovary Shift Across Environmental Factors.Journal of experimental zoology. Part A, Ecological and integrative physiology · 2025Article
- TRF1 and TRF2 form distinct shelterin subcomplexes at telomeres.Cell reports · 2025Article
- Telomere Maintenance and DNA Repair: A Bidirectional Relationship in Cancer Biology and Therapy.Cancers · 2025Review
- Article
- Recent progress in human telomerase structure and its therapeutic targeting.Frontiers in molecular biosciences · 2025Review
- Beginning at the ends: telomere and telomere-based cancer therapeutics.Molecular genetics and genomics : MGG · 2024Review
- Structural biology of shelterin and telomeric chromatin: the pieces and an unfinished puzzle.Biochemical Society transactions · 2024Review
- Telomeres and SIRT1 as Biomarkers of Gamete Oxidative Stress, Fertility, and Potential IVF Outcome.International journal of molecular sciences · 2024Review
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Human shelterin is a six-subunit complex-composed of TRF1, TRF2, Rap1, TIN2, TPP1, and POT1-that binds telomeres, protects them from the DNA-damage response, and regulates the maintenance of telomeric DNA. Although high-resolution structures have been generated of the individual structured domains within shelterin, the architecture and stoichiometry of the full complex are currently unknown. Here, we report the purification of shelterin subcomplexes and reconstitution of the entire complex using full-length, recombinant subunits. By combining negative-stain electron microscopy (EM), cross-linking mass spectrometry (XLMS), AlphaFold modeling, mass photometry, and native mass spectrometry (MS), we obtain stoichiometries as well as domain-scale architectures of shelterin subcomplexes and determine that they feature extensive conformational heterogeneity. For POT1/TPP1 and POT1/TPP1/TIN2, we observe high variability in the positioning of the POT1 DNA-binding domain, the TPP1 oligonucleotide/oligosaccharide-binding (OB) fold, and the TIN2 TRFH domain with respect to the C-terminal domains of POT1. Truncation of unstructured linker regions in TIN2, TPP1, and POT1 did not reduce the conformational variability of the heterotrimer. Shelterin and TRF1-containing subcomplexes form fully dimeric stoichiometries, even in the absence of DNA substrates. Shelterin and its subcomplexes showed extensive conformational variability, regardless of the presence of DNA substrates. We conclude that shelterin adopts a multitude of conformations and argue that its unusual architectural variability is beneficial for its many functions at telomeres.
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