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

Nat Commun. 2017 Apr 10:8:14928. doi: 10.1038/ncomms14928.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Calorimetry
  • Crystallography, X-Ray
  • DNA / metabolism
  • HEK293 Cells
  • Humans
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Protein Binding
  • Shelterin Complex / chemistry*
  • Shelterin Complex / metabolism*
  • Structure-Activity Relationship
  • Telomerase / metabolism
  • Telomere / chemistry*
  • Telomere / metabolism*
  • Telomere-Binding Proteins / chemistry*
  • Telomere-Binding Proteins / genetics
  • Telomere-Binding Proteins / metabolism*

Substances

  • ACD protein, human
  • Mutant Proteins
  • POT1 protein, human
  • Shelterin Complex
  • Telomere-Binding Proteins
  • DNA
  • Telomerase