Aureli, Simone Cardenas, Vince Bart Raniolo, Stefano Limongelli, Vittorio 2023 The Shelterin complex protein TPP1 interacts with human telomerase (TERT) by means of the TEL-patch region, controlling telomere homeostasis. Aberrations in the TPP1-TERT heterodimer formation might lead to short telomeres and severe diseases like dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. In the present study, we provide a thorough characterization of the structural properties of the TPP1’s OB-domain by combining data coming from microsecond-long molecular dynamics calculations, time-series analyses, and graph-based networks. Our results show that the TEL-patch conformational freedom is influenced by a network of long-range amino acid communications that together determine the proper TPP1-TERT binding. Furthermore, we reveal that in TPP1 pathological variants Glu169Δ, Lys170Δ and Leu95Gln, the TEL-patch plasticity is reduced, affecting the correct binding to TERT and, in turn, telomere processivity, which eventually leads to accelerated aging of affected cells. Our study provides a structural basis for the design of TPP1-targeting ligands with therapeutic potential against cancer and telomeropathies. application/pdf https://susi.usi.ch/global/documents/328295 https://localhost:5000/ark:/12658/srd1328295 https://susi.usi.ch/documents/328295/files/Limongelli_2023_commchem.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s42004-023-01040-y info:eu-repo/semantics/altIdentifier/ark/12658/srd1328295 info:eu-repo/semantics/openAccess CC BY Communications chemistry. - 2023, vol. 6, no. 242 Computational chemistry Molecular dynamics Oncogene proteins Proteins info:eu-repo/classification/udc/54 Conformational plasticity and allosteric communication networks explain Shelterin protein TPP1 binding to human telomerase http://purl.org/coar/resource_type/c_6501