5H65

Crystal structure of human POT1 and TPP1

Summary for 5H65

• Entry DOI: 10.2210/pdb5h65/pdb
• Descriptor: Protection of telomeres protein 1, Adrenocortical dysplasia protein homolog, ZINC ION, ... (4 entities in total)
• Functional Keywords: telomere, dna binding protein, ob fold
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus : Q9NUX5 Q96AP0
• Total number of polymer chains: 2
• Total formula weight: 38810.01

Authors

Chen, C.,Wu, J.,Lei, M. (deposition date: 2016-11-10, release date: 2017-05-31, Last modification date: 2024-03-20)

Primary citation

Chen, C.,Gu, P.,Wu, J.,Chen, X.,Niu, S.,Sun, H.,Wu, L.,Li, N.,Peng, J.,Shi, S.,Fan, C.,Huang, M.,Wong, C.C.,Gong, Q.,Kumar-Sinha, C.,Zhang, R.,Pusztai, L.,Rai, R.,Chang, S.,Lei, M.
Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer.
Nat Commun, 8:14929-14929, 2017

PubMed Abstract: Mammalian shelterin proteins POT1 and TPP1 form a stable heterodimer that protects chromosome ends and regulates telomerase-mediated telomere extension. However, how POT1 interacts with TPP1 remains unknown. Here we present the crystal structure of the C-terminal portion of human POT1 (POT1C) complexed with the POT1-binding motif of TPP1. The structure shows that POT1C contains two domains, a third OB fold and a Holliday junction resolvase-like domain. Both domains are essential for binding to TPP1. Notably, unlike the heart-shaped structure of ciliated protozoan Oxytricha nova TEBPα-β complex, POT1-TPP1 adopts an elongated V-shaped conformation. In addition, we identify several missense mutations in human cancers that disrupt the POT1C-TPP1 interaction, resulting in POT1 instability. POT1C mutants that bind TPP1 localize to telomeres but fail to repress a DNA damage response and inappropriate repair by A-NHEJ. Our results reveal that POT1 C terminus is essential to prevent initiation of genome instability permissive for tumorigenesis.

PubMed: 28393832
DOI: 10.1038/ncomms14929

Experimental method

X-RAY DIFFRACTION (2.1 Å)