Aureli Simone, Cardenas Vince Bart, Raniolo Stefano, Limongelli Vittorio
Faculty of Biomedical Sciences, Euler Institute, Università della Svizzera italiana (USI), via G. Buffi 13, Lugano, CH-6900, Switzerland.
Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneve, Rue Michel-Servet 1, Geneva, CH-1211, Switzerland.
Commun Chem. 2023 Nov 7;6(1):242. doi: 10.1038/s42004-023-01040-y.
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.
端粒保护蛋白复合体蛋白TPP1通过TEL-结构域与人类端粒酶（TERT）相互作用，控制端粒稳态。TPP1-TERT异二聚体形成异常可能导致端粒缩短以及诸如先天性角化不良和霍耶拉尔-赫雷迪松综合征等严重疾病。在本研究中，我们结合微秒级分子动力学计算、时间序列分析和基于图的网络数据，对TPP1的OB结构域的结构特性进行了全面表征。我们的结果表明，TEL-结构域的构象自由度受长程氨基酸通讯网络的影响，该网络共同决定了TPP1与TERT的正确结合。此外，我们发现，在TPP1的病理变体Glu169Δ、Lys170Δ和Leu95Gln中，TEL-结构域的可塑性降低，影响了与TERT的正确结合，进而影响端粒的延伸能力，最终导致受影响细胞加速衰老。我们的研究为设计具有治疗癌症和端粒疾病潜力的靶向TPP1的配体提供了结构基础。
