TRF-binding motif region of TRF-Interacting Nuclear factor 2
The C-terminal region of TIN2 contains the TRF-binding motif (TBM), while the TIN2 N-terminal region acts in the modulation of TRF1 activity via the inhibition of tankyrase 1. TIN2 binding to TRF2 is primarily via the TRF binding motif (TBM) and the N-terminus, while the far C-terminal region interacts with lower affinity. The TIN2 TBM, but not the N-terminal region, is involved in TIN2 binding to TRF1. Truncation of the TIN2 N-terminus in mouse results in telomere elongation, suggesting a a negative regulatory function of this region. TIN2 is a shelterin complex protein identified in mammals, one of 6 factors that act to protect telomeres from DNA damage repair machinery. Three shelterin components (TRF1, TRF2, POT1) bind DNA and 3 components (TIN2, RAP1, TPP1) are recruited by these DNA binding factors. TIN2 binds directly to TRF1 and TRF2 and stabilizes TRF2 complex-telomere binding by tethering it to the TRF1 complex. TRF1 activity at telomeres is regulated in part by selective ubiquitination and degradation. Ubiquitination of TRF1 is mediated by Fbx4, which binds TRF1 in the TRFH domain, via a small GTPase module. When bound to telomeres, TIN2 acts to protect TRF1 from SCF-Fbx4 mediated ubiquitination. F-box proteins act in substrate recognition as part of SCF complexes (SCF: Skp1-Cul1-Rbx1-F- box protein). Tankyrase-mediated ADP-ribosylation releases TRF1 from telomeres, rendering them susceptible to ubiquitination and degradation, promoting telomere elongation. TIN2 also binds TPP1, which recruits POT1 to telomeres.
Comment:[FY]xLxP TRF binding motif is shared by TIN2, PinX1 and Apollo
Comment:contacts based on comparison to PDB 3BQO, in which a peptide corresponding to a.a. 257-276 (hfnlaplgrrrvqsqwastr) of human TIN2 binds the TRF1 TRFH domain
Jiyao W et al.(2023). "The conserved domain database in 2023.",