Conformational plasticity and allosteric communication networks explain Shelterin protein TPP1 binding to human telomerase
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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
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Cardenas, Vince Bart
Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Raniolo, Stefano
ORCID
Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Limongelli, Vittorio
ORCID
Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Published in:
- Communications chemistry. - 2023, vol. 6, no. 242
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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Chemistry
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CC BY
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Open access status
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gold
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Persistent URL
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https://n2t.net/ark:/12658/srd1328295
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