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Limongelli_2023_commchem
Journal article

Conformational plasticity and allosteric communication networks explain Shelterin protein TPP1 binding to human telomerase

  • Aureli, Simone ORCID Euler Institute (EUL), Università della Svizzera italiana, Switzerland - Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneve, Geneva, Switzerland - Swiss Institute of Bioinformatics, University of Geneve, Geneva , Switzerland
  • Cardenas, Vince Bart Euler Institute (EUL), Università della Svizzera italiana, Switzerland
  • Raniolo, Stefano ORCID Euler Institute (EUL), Università della Svizzera italiana, Switzerland
  • Limongelli, Vittorio ORCID Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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  • 2023
Published in:
  • Communications chemistry. - 2023, vol. 6, no. 242
Computational chemistry
Molecular dynamics
Oncogene proteins
Proteins
English 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.
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Language
  • English
Classification
Chemistry
License
CC BY
Open access status
gold
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Persistent URL
https://n2t.net/ark:/12658/srd1328295
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