5xyf
From Proteopedia
Crystal structure of the human TIN2-TPP1-TRF2 telomeric complex
Structural highlights
DiseaseTINF2_HUMAN Defects in TINF2 are a cause of dyskeratosis congenita autosomal dominant type 3 (DKCA3) [MIM:613990. A rare multisystem disorder caused by defective telomere maintenance. It is characterized by progressive bone marrow failure, and the clinical triad of reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia. Common but variable features include premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, and liver fibrosis among others. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy.[1] Defects in TINF2 are a cause of retinopathy exudative with bone marrow failure (ERBMF) [MIM:268130; also known as Revesz syndrome. ERBMF is characterized by bilateral exudative retinopathy, bone marrow hypoplasia, nail dystrophy, fine hair, cerebellar hypoplasia, and growth retardation.[2] FunctionTINF2_HUMAN Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection. Shelterin associates with arrays of double-stranded TTAGGG repeats added by telomerase and protects chromosome ends; without its protective activity, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. Plays a role in shelterin complex assembly. Isoform 1 may have additional role in tethering telomeres to the nuclear matrix.[3] [4] [5] Publication Abstract from PubMedTelomeres 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. Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex.,Hu C, Rai R, Huang C, Broton C, Long J, Xu Y, Xue J, Lei M, Chang S, Chen Y Cell Res. 2017 Dec;27(12):1485-1502. doi: 10.1038/cr.2017.144. Epub 2017 Nov 21. PMID:29160297[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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