Journal Article

Structural and functional analysis of the human POT1-TPP1 telomeric complex

Baird, Duncan M., Kossenkov, Andrew V., Hills, Robert, Doukov, Tzanko, Rice, Cory, Showe, Louise C., Janicki, Susan, Shastrula, Prashanth Krishna, Skordalakes, Emmanuel

2017

Overview

POT1 and TPP1 are part of the shelterin complex and are essential for telomere length regulation and maintenance. Naturally occurring mutations of the telomeric POT1–TPP1 complex are implicated in familial glioma, melanoma and chronic lymphocytic leukaemia. Here we report the atomic structure of the interacting portion of the human telomeric POT1–TPP1 complex and suggest how several of these mutations contribute to malignant cancer. The POT1 C-terminus (POT1C) forms a bilobal structure consisting of an OB-fold and a holiday junction resolvase domain. TPP1 consists of several loops and helices involved in extensive interactions with POT1C. Biochemical data shows that several of the cancer-associated mutations, partially disrupt the POT1–TPP1 complex, which affects its ability to bind telomeric DNA efficiently. A defective POT1–TPP1 complex leads to longer and fragile telomeres, which in turn promotes genomic instability and cancer. POT1 and TTP1 are part of the shelterin complex that caps and stabilizes the ends of telomeres. Here the authors present a structural analysis of the human POT1-TTP1 complex, shedding light on how it assembles and how cancer-associated mutations impact its assembly and function.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 14 / 14/19 / 14/35 / 38 / 38/1 / 38/32 / 38/70 / 45 / 45/77 / 631/535/1266 / 631/80/103/560 / 631/80/304 / 64 / 82/80 / 82/83 / Calorimetry / Cancer / Cell cycle / Chromosomes / Crystallography, X-Ray / DNA - metabolism / DNA damage / HEK293 Cells / Humanities and Social Sciences / Humans / Leukemia / Mechanisms of disease / Melanoma / multidisciplinary / Mutant Proteins - metabolism / Mutation / Mutation - genetics / Protein Binding / Proteins / Science / Science (multidisciplinary) / Shelterin Complex - chemistry / Shelterin Complex - metabolism / Structure-Activity Relationship / Telomerase / Telomerase - metabolism / Telomere - chemistry / Telomere - metabolism / Telomere-Binding Proteins - chemistry / Telomere-Binding Proteins - genetics / Telomere-Binding Proteins - metabolism / Telomeres / X-ray crystallography / Yeast