Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease.
Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease.
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DOI：
10.1038/s41598-023-50932-5
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发表时间：
2024-01-09
影响因子：
4.6
通讯作者：
Chang, Iksoo
中科院分区：
文献类型：
--
作者：
Lee, Juhwan;Sim, Kyoung Mi;Kang, Mooseok;Oh, Hyun Ju;Choi, Ho Jung;Kim, Yeong Eun;Pack, Chan-Gi;Kim, Kyunggon;Kim, Kyung Mo;Oh, Seak Hee;Kim, Inki;Chang, Iksoo
X连锁凋亡抑制蛋白（XIAP）缺乏导致难治性炎症性肠病。XIAP蛋白通过含核苷酸结合寡聚化结构域的信号通路在促炎反应中起关键作用，该信号通路在粘膜稳态中是重要的。我们分析了XIAP BIR 2结构域的非同义致病变体（PV）的分子机制。我们产生了代表性的非同义PV的N-末端绿色荧光蛋白标记的XIAP构建体。免疫共沉淀和荧光交叉相关光谱显示，野生型XIAP和RIP 2优先在活细胞中相互作用，而所有非同义的PV XIAP未能正确地与RIP 2相互作用。结构分析表明，突变引起的各种结构变化，如疏水核心塌陷、锌指缺失和空间重排，使与RIP 2关键相互作用的两个环结构（174-182和205-215）不稳定。随后，它导致RIP 2泛素化的失败和所有XIAP突变体的自身泛素化导致蛋白质缺陷的丧失。这些发现可以增强我们对XIAP突变在XIAP缺陷型炎症性肠病中的作用的理解，并可能有利于未来的治疗策略。
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.
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影响因子：
4
作者：
Dubrez L;Berthelet J;Glorian V
通讯作者：
Glorian V
影响因子：
4.8
作者：
Kim, Hye-Jin;Kwon, Sojung;Lee, Jung Weon
通讯作者：
Lee, Jung Weon
DOI：
10.1002/prot.10276
发表时间：
2003-02-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Eyal, E;Najmanovich, R;Sobolev, V
通讯作者：
Sobolev, V
影响因子：
12.4
作者：
Makhov, P.;Golovine, K.;Uzzo, R. G.;Rothman, J.;Crispen, P. L.;Shaw, T.;Scoll, B. J.;Kolenko, V. M.
通讯作者：
Kolenko, V. M.
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG