Telomeres are specialized structures located at the ends of linear chromosomes essential for cell viability and genome integrity. Their protective function is due to the formation of the Shelterin complex, that caps the end of the DNA. In the mammalian complex, Telomeric Repeat-binding Factor 2 (TRF2) interacts with TRF2-interacting protein 1 (RAP1).
We previously showed by ITC that TRF2-RAP1 interaction involves a complex biphasic mechanism . RAP1, as TRF2, is a multidomain protein, comprising a N-terminal domain with sequence similarity to BRCT domains (RAP1[BRCT]), a central pseudo-Myb domain and a C-terminal domain that binds with high affinity with the so-called RAP1-binding domain of TRF2. The function of the RAP1[BRCT] is not yet assigned.
Here we report a structural analysis of the binding between the different domains of RAP1 and TRF2. First, we solved the solution structure of RAP1[1-114] that belongs to BRCT domain family. The conformation of the YRLGP sequence in RAP1[1-114] is well defined and similar to that adopted in a 14-mer peptide crystallized in complex with the dimeric TRFH domain of TRF2 . This led us to build a RAP1[1-114]-TRFH dimer model. However, we showed by NMR that the isolated RAP1[1-114] domain is not able to interact with TRFH. This observation seemed a priori in contradiction with ITC data previously obtained to characterize the interaction of the full form of RAP1 with TRF2. However, re-examination of ITC and NMR interaction data obtained with truncated forms of the two proteins permitted to reconcile these data in the light of the divalent thermodynamics interaction model . The cooperative mechanism revealed by this analysis could contribute to regulate the interaction of TRF2 with partners interacting via YRLGP-like peptides.
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