title: A comprehensive model for the recognition of human telomeres by TRF1.
abstract: Eukaryotic chromosomes are capped by telomeres, nucleoprotein complexes that prevent chromosome end-to-end fusions and control cell ageing. Two proteins in this complex, telomere repeat binding factors (TRF1 and TRF2), specifically recognise the double-stranded TTAGGG tandem repeat sequence. TRF1 is a homodimer with roles governing DNA architecture and negatively regulating telomere length. We explore the conformational space of this protein-DNA complex using molecular dynamics and, for the first time, generate a complete model of TRF1-DNA recognition that has not been possible on the basis of crystallographic and NMR data alone. The results reconcile previous conflicting experimental models for the sequence selectivity of the recognition process, by confirming many of the findings while identifying important new interactions and behaviour. This improved characterisation also reveals extensive indirect readout, which suggests that recognition will be affected by changes to DNA helical parameters such as bending.
authors.affiliation: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Garton
authors.forename: Charles
authors.initials: C
authors.lastname: Laughton
mesh_terms: D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011487:Protein Conformation; D016615:Telomere / Q000737:chemistry* / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D035321:Telomeric Repeat Binding Protein 1
keywords: HTH; MD; PCA; dynamics; helix–turn–helix; interaction; map; molecular dynamics; principal component analysis; simulation; telomeric