Volume 27, No 12, Dec 2017
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 27 Issue 12, December 2017: 1485-1502
ORIGINAL ARTICLES
Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex
Chunyi Hu1,*, Rekha Rai2,*, Chenhui Huang3,4, Cayla Broton2, Juanjuan Long1, Ying Xu1, Jing Xue1, Ming Lei3,4,5, Sandy Chang2,6,7, Yong Chen1,8
1State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China;
2Department of Laboratory Medicine, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06510 USA;
3Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China;
4Shanghai Institute of Precision Medicine, Shanghai 200125, China;
5Key laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
6Department of Pathology, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06510 USA;
7Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 330 Cedar St., New Haven, CT 06510 USA;
8School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
Correspondence: Yong Chen, E-mail: yongchen@sibcb.ac.cn; Sandy Chang, E-mail: s.chang@yale.edu; Ming Lei,(leim@shsmu.edu.cn)
Telomeres are nucleoprotein complexes that play essential roles in protecting chromosome ends. Mammalian telomeres consist of repetitive DNA sequences bound by the shelterin complex. In this complex, the POT1-TPP1 heterodimer binds to single-stranded telomeric DNAs, while TRF1 and TRF2-RAP1 interact with double-stranded telomeric DNAs. TIN2, the linchpin of this complex, simultaneously interacts with TRF1, TRF2, and TPP1 to mediate the stable assembly of the shelterin complex. However, the molecular mechanism by which TIN2 interacts with these proteins to orchestrate telomere protection remains poorly understood. Here, we report the crystal structure of the N-terminal domain of TIN2 in complex with TIN2-binding motifs from TPP1 and TRF2, revealing how TIN2 interacts cooperatively with TPP1 and TRF2. Unexpectedly, TIN2 contains a telomeric repeat factor homology (TRFH)-like domain that functions as a protein-protein interaction platform. Structure-based mutagenesis analyses suggest that TIN2 plays an important role in maintaining the stable shelterin complex required for proper telomere end protection.
10.1038/cr.2017.144
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