Rab8a is associated with the dynamic regulation of membrane protrusions in polarized cells. Rab8a is one of several Rab GTPases that are substrates of leucine-rich repeat kinase 2 (LRRK2), a serine/threonine kinase that is linked to Parkinson's disease. Rab8a is phosphorylated at T72 (pT72) in its switch 2 helix and recruits the phospho-specific effector RILPL2, which subsequently regulates ciliogenesis. Here, we report the crystal structure of phospho-Rab8a (pRab8a) in complex with the RH2 (RILP homology) domain of RILPL2. The complex is a heterotetramer with RILPL2 forming a central α-helical dimer that bridges two pRab8a molecules. The N termini of the α helices cross over, forming an X-shaped cap (X-cap) that orients Arg residues from RILPL2 toward pT72. X-cap residues critical for pRab8a binding are conserved in JIP3 and JIP4, which also interact with LRRK2-phosphorylated Rab10. We propose a general mode of recognition for phosphorylated Rab GTPases by this family of phospho-specific effectors.

中文翻译：

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Rab8a 通过开关 2 的 LRRK2 磷酸化招募 RILPL2 的结构基础。


Rab8a 与极化细胞中膜突起的动态调节有关。 Rab8a 是几种 Rab GTP 酶之一，是富含亮氨酸重复激酶 2 (LRRK2) 的底物，LRRK2 是一种与帕金森病相关的丝氨酸/苏氨酸激酶。 Rab8a 在其开关 2 螺旋的 T72 (pT72) 处被磷酸化，并招募磷酸特异性效应子 RILPL2，随后调节纤毛发生。在这里，我们报道了与 RILPL2 的 RH2（RILP 同源）结构域复合的磷酸化 Rab8a (pRab8a) 的晶体结构。该复合物是一个异四聚体，RILPL2 形成一个中心 α-螺旋二聚体，桥接两个 pRab8a 分子。 α 螺旋的 N 末端交叉，形成 X 形帽 (X-cap)，将 RILPL2 的精氨酸残基定向到 pT72。对于 pRab8a 结合至关重要的 X-cap 残基在 JIP3 和 JIP4 中是保守的，它们也与 LRRK2 磷酸化的 Rab10 相互作用。我们提出了该磷酸化特异性效应子家族识别磷酸化 Rab GTP 酶的通用模式。