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

Simone Aureli; Vince Bart Cardenas; Stefano Raniolo; Vittorio Limongelli

doi:10.1038/s42004-023-01040-y

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

Commun Chem. 2023 Nov 7;6(1):242. doi: 10.1038/s42004-023-01040-y.

Authors

Simone Aureli^#^{1

2

3}, Vince Bart Cardenas^#¹, Stefano Raniolo^#¹, Vittorio Limongelli⁴

Affiliations

¹ Faculty of Biomedical Sciences, Euler Institute, Università della Svizzera italiana (USI), via G. Buffi 13, Lugano, CH-6900, Switzerland.
² Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneve, Rue Michel-Servet 1, Geneva, CH-1211, Switzerland.
³ Swiss Institute of Bioinformatics, University of Geneve, Geneva, CH-1206, Switzerland.
⁴ Faculty of Biomedical Sciences, Euler Institute, Università della Svizzera italiana (USI), via G. Buffi 13, Lugano, CH-6900, Switzerland. vittoriolimongelli@gmail.com.

^# Contributed equally.

Abstract

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.

Abstract

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