Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms.
Structural and functional plasticity of subcellular tethering, targeting and processing of RPGRIP1 by RPGR isoforms.
复制标题
DOI：
10.1242/bio.2011489
复制
发表时间：
2012-02-15
期刊：
影响因子：
2.4
通讯作者：
Ferreira PA
中科院分区：
文献类型：
--
作者：
Patil H;Guruju MR;Cho KI;Yi H;Orry A;Kim H;Ferreira PA
影响色素性视网膜炎 GTP 酶调节相互作用蛋白 1 (RPGRIP1) 相互作用组的突变会导致综合征性视网膜营养不良。 RPGRIP1 通过与 RCC1 (RHD)（Ran GTPase 的核苷酸交换因子）同源的结构域与视网膜色素变性 GTPase 调节剂 (RPGR) 相互作用。然而，RPGR 和 RPGRIP1 之间的功能关系及其亚细胞作用尚不清楚。我们通过 RPGR 疾病突变的分子建模和分析表明，RPGRIP1 的 RPGR 相互作用域 (RID) 多价包含 RPGR1-19 和 RPGRORF15 亚型的共享 RHD，并且突变与 RCC1 和 Ran GTPase 之间发现的界面不重叠。 RPGR 疾病突变根据其结构位置和 RPGRIP1 相互作用的不同损伤分为六类。 RPGRIP1α1 单独表达会导致其大量的自聚集，这种效应在 RPGRIP1α1 自聚集发生之前和之后被任一 RPGR 同工型的共表达所抑制。 RPGR1-19 定位于内质网，而 RPGRORF15 呈现细胞质分布，它们独特地决定了 RPGRIP1α1 的亚细胞共定位。 RPGR1-19、RPGRORF15 或 RPGRIP1α1 的 RID 中的疾病突变，单独或组合，对肾脏、光感受器和肝细胞系中 RPGRIP1α1 与 RPGR1-19 或 RPGRORF15 的亚细胞靶向、共定位或束缚产生不同的影响。此外，RPGRORF15（但不是 RPGR1-19）可以保护 RPGRIP1α1 的 RID 免受有限的蛋白水解。这些研究定义了 RPGR 和细胞类型依赖性靶向途径，其结构和功能可塑性调节 RPGR 和 RPGRIP1 突变的表达。此外，RPGR 同种型独特地决定了 RPGRIP1α1 的亚细胞靶向，RPGRIP1α1 依赖于 RPGRORF15 的细胞内定位缺陷导致了病因不同的综合征性视网膜营养不良所共有的病理机制。
Mutations affecting the retinitis pigmentosa GTPase regulator-interacting protein 1 (RPGRIP1) interactome cause syndromic retinal dystrophies. RPGRIP1 interacts with the retinitis pigmentosa GTPase regulator (RPGR) through a domain homologous to RCC1 (RHD), a nucleotide exchange factor of Ran GTPase. However, functional relationships between RPGR and RPGRIP1 and their subcellular roles are lacking. We show by molecular modeling and analyses of RPGR disease-mutations that the RPGR-interacting domain (RID) of RPGRIP1 embraces multivalently the shared RHD of RPGR1–19 and RPGRORF15 isoforms and the mutations are non-overlapping with the interface found between RCC1 and Ran GTPase. RPGR disease-mutations grouped into six classes based on their structural locations and differential impairment with RPGRIP1 interaction. RPGRIP1α1 expression alone causes its profuse self-aggregation, an effect suppressed by co-expression of either RPGR isoform before and after RPGRIP1α1 self-aggregation ensue. RPGR1–19 localizes to the endoplasmic reticulum, whereas RPGRORF15 presents cytosolic distribution and they determine uniquely the subcellular co-localization of RPGRIP1α1. Disease mutations in RPGR1–19, RPGRORF15, or RID of RPGRIP1α1, singly or in combination, exert distinct effects on the subcellular targeting, co-localization or tethering of RPGRIP1α1 with RPGR1–19 or RPGRORF15 in kidney, photoreceptor and hepatocyte cell lines. Additionally, RPGRORF15, but not RPGR1–19, protects the RID of RPGRIP1α1 from limited proteolysis. These studies define RPGR- and cell-type-dependent targeting pathways with structural and functional plasticity modulating the expression of mutations in RPGR and RPGRIP1. Further, RPGR isoforms distinctively determine the subcellular targeting of RPGRIP1α1, with deficits in RPGRORF15-dependent intracellular localization of RPGRIP1α1 contributing to pathomechanisms shared by etiologically distinct syndromic retinal dystrophies.
登录
查看更多内容
影响因子：
9.8
作者：
Breuer, DK;Yashar, BM;Swaroop, A
通讯作者：
Swaroop, A
影响因子：
3.7
作者：
Fahim AT;Bowne SJ;Sullivan LS;Webb KD;Williams JT;Wheaton DK;Birch DG;Daiger SP
通讯作者：
Daiger SP
影响因子：
5.3
作者：
Apolloni, A;Prior, IA;Hancock, JF
通讯作者：
Hancock, JF
影响因子：
3.5
作者：
Castagnet, P;Mavlyutov, T;Ferreira, P
通讯作者：
Ferreira, P
影响因子：
5.6
作者：
ABAGYAN, R;TOTROV, M
通讯作者：
TOTROV, M