title: Molecular basis and quantitative assessment of TRF1 and TRF2 protein interactions with TIN2 and Apollo peptides.
abstract: Shelterin is a six-protein complex (TRF1, TRF2, POT1, RAP1, TIN2, and TPP1) that also functions in smaller subsets in regulation and protection of human telomeres. Two closely related proteins, TRF1 and TRF2, make high-affinity contact directly with double-stranded telomeric DNA and serve as a molecular platform. Protein TIN2 binds to TRF1 and TRF2 dimer-forming domains, whereas Apollo makes interaction only with TRF2. To elucidate the molecular basis of these interactions, we employed molecular dynamics (MD) simulations of TRF1TRFH-TIN2TBMand TRF2TRFH-TIN2TBM/ApolloTBMcomplexes and of the isolated proteins. MD enabled a structural and dynamical comparison of protein-peptide complexes including H-bond interactions and interfacial residues that may regulate TRF protein binding to the given peptides, especially focusing on interactions described in crystallographic data. Residues with a selective function in both TRF1TRFHand TRF2TRFHand forming a stable hydrogen bond network with TIN2TBMor ApolloTBMpeptides were traced. Our study revealed that TIN2TBMforms a well-defined binding mode with TRF1TRFHas compared to TRF2TRFH, and that the binding pocket of TIN2TBMis deeper for TRF2TRFHprotein than ApolloTBM. The MD data provide a basis for the reinterpretation of mutational data obtained in crystallographic work for the TRF proteins. Together, the previously determined X-ray structure and our MD provide a detailed view of the TRF-peptide binding mode and the structure of TRF1/2 binding pockets. Particular TRF-peptide interactions are very specific for the formation of each protein-peptide complex, identifying TRF proteins as potential targets for the design of inhibitors/drugs modulating telomere machinery for anticancer therapy.
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233, Gdansk, Poland. umekalat@gmail.com.
authors.forename: Umesh
authors.initials: U
authors.lastname: Kalathiya
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233, Gdansk, Poland.
authors.forename: Monikaben
authors.initials: M
authors.lastname: Padariya
authors.affiliation: Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233, Gdansk, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Baginski
mesh_terms: D045643:DNA Repair Enzymes / Q000737:chemistry* / Q000378:metabolism; D005090:Exodeoxyribonucleases; D006801:Humans; D056004:Molecular Dynamics Simulation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D035321:Telomeric Repeat Binding Protein 1 / Q000737:chemistry* / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000737:chemistry* / Q000378:metabolism
chemical_list: C495876:ACD protein, human; D009687:Nuclear Proteins; D010455:Peptides; D000089804:Shelterin Complex; C504753:TERF2 protein, human; C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins; D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2; C493741:DCLRE1B protein, human; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes
keywords: Apollo; Molecular dynamics; Shelterin complex; TIN2; TRF1; TRF2