Mistrafficking of prenylated proteins causes retinitis pigmentosa 2
Mistrafficking of prenylated proteins causes retinitis pigmentosa 2
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异戊二烯化蛋白的错误运输会导致色素性视网膜炎 2。
DOI：
10.1096/fj.14-257915
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发表时间：
2015-03-01
期刊：
影响因子：
4.8
通讯作者：
Baehr, Wolfgang
中科院分区：
文献类型：
--
作者：
Zhang, Houbin;Hanke-Gogokhia, Christin;Baehr, Wolfgang
视网膜色素变性2多肽（RP 2）作为一种GTP酶激活蛋白（GAP），用于ARL 3（Arf样蛋白3），一种小的GTP酶。ARL 3是磷酸二酯酶6 δ（PDE 6D）的效应子，PDE 6D是光感受器中异戊二烯基结合蛋白和异戊二烯化蛋白的伴侣。人类RP 2基因突变导致X连锁视网膜色素变性（XLRP）和视锥-视杆细胞营养不良（XL-CORD）。为了研究引起XLRP的机制，我们产生了RP 2敲除小鼠。RP 2 h（-/-）小鼠表现出模拟人类疾病的缓慢进展的视杆-视锥营养不良。RP 2 h（-/-）暗视a波和明视b波振幅在1个月龄时下降，并在接下来的6个月内继续下降。异戊烯化的PDE 6亚基和G蛋白偶联受体激酶1（GRK 1）不能有效地运输到RP 2 h（-/-）外段。从机制上讲，RP 2 GAP活性的缺乏增加了ARL 3-GTP水平，迫使PDE 6D呈现主要的“闭合”构象，阻碍脂质的结合。缺乏相互作用会破坏PDE 6和GRK 1向其目的地（光感受器外节）的运输。我们提出，在RP 2基因敲除小鼠和RP 2无效等位基因的人类患者中，ARL 3-GTP的过度活跃导致XLRP类似于隐性视杆细胞-视锥细胞营养不良。
The retinitis pigmentosa 2 polypeptide (RP2) functions as a GTPase-activating protein (GAP) for ARL3 (Arf-like protein 3), a small GTPase. ARL3 is an effector of phosphodiesterase 6 Delta (PDE6D), a prenyl-binding protein and chaperone of prenylated protein in photoreceptors. Mutations in the human RP2 gene cause X-linked retinitis pigmentosa (XLRP) and cone-rod dystrophy (XL-CORD). To study mechanisms causing XLRP, we generated an RP2 knockout mouse. The RP2h(-/-) mice exhibited a slowly progressing rod-cone dystrophy simulating the human disease. RP2h(-/-) scotopic a-wave and photopic b-wave amplitudes declined at 1 mo of age and continued to decline over the next 6 mo. Prenylated PDE6 subunits and G-protein coupled receptor kinase 1 (GRK1) were unable to traffic effectively to the RP2h(-/-) outer segments. Mechanistically, absence of RP2 GAP activity increases ARL3-GTP levels, forcing PDE6D to assume a predominantly "closed" conformation that impedes binding of lipids. Lack of interaction disrupts trafficking of PDE6 and GRK1 to their destination, the photoreceptor outer segments. We propose that hyperactivity of ARL3-GTP in RP2 knockout mice and human patients with RP2 null alleles leads to XLRP resembling recessive rod-cone dystrophy.