title: Structural and functional analysis of the human POT1-TPP1 telomeric complex.
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.
authors.affiliation: The Wistar Institute, 3601 Spruce St, Philadelphia, Pennsylvania 19104, USA.|Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Cory
authors.initials: C
authors.lastname: Rice
authors.affiliation: The Wistar Institute, 3601 Spruce St, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Prashanth Krishna
authors.initials: PK
authors.lastname: Shastrula
authors.affiliation: The Wistar Institute, 3601 Spruce St, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: The Wistar Institute, 3601 Spruce St, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Hills
authors.affiliation: Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF10 3AT, UK.
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Baird
authors.affiliation: The Wistar Institute, 3601 Spruce St, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Louise C
authors.initials: LC
authors.lastname: Showe
authors.affiliation: Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, California 94025, USA.
authors.forename: Tzanko
authors.initials: T
authors.lastname: Doukov
authors.affiliation: The Wistar Institute, 3601 Spruce St, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Janicki
authors.affiliation: The Wistar Institute, 3601 Spruce St, Philadelphia, Pennsylvania 19104, USA.|Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Skordalakes
mesh_terms: D002151:Calorimetry; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D000089804:Shelterin Complex / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000737:chemistry* / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C495876:ACD protein, human; D050505:Mutant Proteins; C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D004247:DNA; D019098:Telomerase