4YNQ

TREX1-dsDNA complex

4YNQ の概要

• エントリーDOI: 10.2210/pdb4ynq/pdb
• 分子名称: Three-prime repair exonuclease 1, DNA (24-MER), DNA (5'-D(P*GP*TP*GP*CP*TP*GP*AP*CP*GP*TP*CP*AP*GP*CP*AP*CP*GP*AP*CP*G)-3'), ... (6 entities in total)
• 機能のキーワード: protein-dna complex, exonuclease, trex1, hydrolase-dna complex, hydrolase/dna
• 由来する生物種: Mus musculus (Mouse); 詳細
• 細胞内の位置: Nucleus: Q91XB0
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 128410.97

構造登録者

Fye, J.M.,Harvey, S.,Perrino, F.W.,Hollis, T. (登録日: 2015-03-10, 公開日: 2015-05-27, 最終更新日: 2025-02-12)

主引用文献

Grieves, J.L.,Fye, J.M.,Harvey, S.,Grayson, J.M.,Hollis, T.,Perrino, F.W.
Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease.
Proc.Natl.Acad.Sci.USA, 112:5117-5122, 2015

PubMed Abstract: The TREX1 gene encodes a potent DNA exonuclease, and mutations in TREX1 cause a spectrum of lupus-like autoimmune diseases. Most lupus patients develop autoantibodies to double-stranded DNA (dsDNA), but the source of DNA antigen is unknown. The TREX1 D18N mutation causes a monogenic, cutaneous form of lupus called familial chilblain lupus, and the TREX1 D18N enzyme exhibits dysfunctional dsDNA-degrading activity, providing a link between dsDNA degradation and nucleic acid-mediated autoimmune disease. We determined the structure of the TREX1 D18N protein in complex with dsDNA, revealing how this exonuclease uses a novel DNA-unwinding mechanism to separate the polynucleotide strands for single-stranded DNA (ssDNA) loading into the active site. The TREX1 D18N dsDNA interactions coupled with catalytic deficiency explain how this mutant nuclease prevents dsDNA degradation. We tested the effects of TREX1 D18N in vivo by replacing the TREX1 WT gene in mice with the TREX1 D18N allele. The TREX1 D18N mice exhibit systemic inflammation, lymphoid hyperplasia, vasculitis, and kidney disease. The observed lupus-like inflammatory disease is associated with immune activation, production of autoantibodies to dsDNA, and deposition of immune complexes in the kidney. Thus, dysfunctional dsDNA degradation by TREX1 D18N induces disease in mice that recapitulates many characteristics of human lupus. Failure to clear DNA has long been linked to lupus in humans, and these data point to dsDNA as a key substrate for TREX1 and a major antigen source in mice with dysfunctional TREX1 enzyme.

PubMed: 25848017
DOI: 10.1073/pnas.1423804112

実験手法

X-RAY DIFFRACTION (2.8 Å)