Conformational plasticity and allosteric communication networks explain Shelterin protein TPP1 binding to human telomerase.
Simone AureliVince Bart CardenasStefano RanioloVittorio LimongelliPublished in: Communications chemistry (2023)
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.
Keyphrases
- molecular dynamics
- amino acid
- density functional theory
- molecular dynamics simulations
- endothelial cells
- binding protein
- small molecule
- induced pluripotent stem cells
- induced apoptosis
- single molecule
- early onset
- copy number
- gene expression
- squamous cell carcinoma
- papillary thyroid
- cell cycle arrest
- electronic health record
- genome wide
- oxidative stress
- drug delivery
- protein protein
- squamous cell
- childhood cancer