It appears you don't have support to open PDFs in this web browser. To view this file, Open with your PDF reader
Abstract
X-linked inhibitor of apoptosis protein (XIAP) deficiency causes refractory inflammatory bowel disease. The XIAP protein plays a pivotal role in the pro-inflammatory response through the nucleotide-binding oligomerization domain-containing signaling pathway that is important in mucosal homeostasis. We analyzed the molecular mechanism of non-synonymous pathogenic variants (PVs) of XIAP BIR2 domain. We generated N-terminally green fluorescent protein-tagged XIAP constructs of representative non-synonymous PVs. Co-immunoprecipitation and fluorescence cross-correlation spectroscopy showed that wild-type XIAP and RIP2 preferentially interacted in live cells, whereas all non-synonymous PV XIAPs failed to interact properly with RIP2. Structural analysis showed that various structural changes by mutations, such as hydrophobic core collapse, Zn-finger loss, and spatial rearrangement, destabilized the two loop structures (174–182 and 205–215) that critically interact with RIP2. Subsequently, it caused a failure of RIP2 ubiquitination and loss of protein deficiency by the auto-ubiquitination of all XIAP mutants. These findings could enhance our understanding of the role of XIAP mutations in XIAP-deficient inflammatory bowel disease and may benefit future therapeutic strategies.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details
1 iProtein Therapeutics Inc., Daejeon, Korea
2 University of Ulsan College of Medicine, Department of Convergence Medicine, Asan Medical Center, Asan Institutes for Life Sciences, Seoul, Korea (GRID:grid.267370.7) (ISNI:0000 0004 0533 4667)
3 iProtein Therapeutics Inc., Daejeon, Korea (GRID:grid.267370.7)
4 University of Ulsan College of Medicine, Department of Pediatrics, Asan Medical Center Children’s Hospital, Seoul, Korea (GRID:grid.267370.7) (ISNI:0000 0004 0533 4667)
5 University of Ulsan College of Medicine, Department of Convergence Medicine, Asan Medical Center, Asan Institutes for Life Sciences, Seoul, Korea (GRID:grid.267370.7) (ISNI:0000 0004 0533 4667); University of Ulsan College of Medicine, Department of Pharmacology, Seoul, Korea (GRID:grid.267370.7) (ISNI:0000 0004 0533 4667)
6 DGIST, Creative Research Initiatives Center for Proteome Biophysics, Department of Brain Sciences and Supercomputing Bigdata Center, Daegu, Korea (GRID:grid.417736.0) (ISNI:0000 0004 0438 6721); DGIST, Department of Brain Sciences and Supercomputing Big Data Center, Daegu, Korea (GRID:grid.417736.0) (ISNI:0000 0004 0438 6721)