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

Abstract

The molecular binding interaction between the Shelterin complex protein TPP1 and human telomerase enzyme (TERT) triggers the telomerase maintenance mechanism that marks cell lifespan. The TPP1s structural element deputed to bind TERT is the OB-domain, which is able to interact with TERTs hTEN (TPP1 binding telomerase domain) through the TEL-patch, a group of amino acids whose mutations provoke harsh pathologies. Indeed, aberrations in the formation of TPP1-TERT het-erodimer can lead to severe diseases like Hoyeraal-Hreidarsson syndrome (HHS), whose patients are affected by short telomeres and extremely poor life expectancy. In the present study, we provide a thorough characterization of the structural properties of the TPP1s OB-domain by combining data coming from microsecond-long molecular dynamics calculations, time-series analyses, and graph-based networks. Our results show that the conformational plasticity of the TPP1s TEL-patch region is influenced by a network of long-range amino acid communications, needed for the proper TPP1-hTEN binding. Furthermore, we reveal that in the Glu169{Delta} and Lys170{Delta} TPP1 variants, responsible for HHS, the plasticity of the TEL-patch region is reduced, affecting the correct binding to hTEN and in turn the telomere processivity, which eventually leads to accelerated ageing of affected cells. Our study provides an unprecedented structural basis for the design of TPP1-targeting ligands with therapeutic potential against cancer and telomerase deficiency diseases.