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

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 Glu169 Delta, Lys170 Delta 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. The binding interaction between the Shelterin complex protein TPP1 and the human telomerase enzyme can trigger telomerase maintenance, however, the conformational change of TPP1 functional for binding remains underexplored. Here, the authors characterize the structural properties of a group of amino acids named the TEL-patch within TPP1's oligosaccharide/oligonucleotide-domain by molecular dynamics simulation, time-series analyses, and graph-based networks, revealing their conformational plasticity and allosteric communication networks.