Kalirin 的 Sec14 结构域揭示了 RhoGEFs 中一类独特的脂质结合模块。
Structure of the Sec14 domain of Kalirin reveals a distinct class of lipid-binding module in RhoGEFs.
机构信息
Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, 06030, USA.
Macromolecular Crystallography Group, Stanford Synchrotron Radiation Light Source, SLAC National Accelerator Laboratory, Stanford University, Stanford, CA, 94309, USA.
出版信息
Nat Commun. 2023 Jan 6;14(1):96. doi: 10.1038/s41467-022-35678-4.
Gated entry of lipophilic ligands into the enclosed hydrophobic pocket in stand-alone Sec14 domain proteins often links lipid metabolism to membrane trafficking. Similar domains occur in multidomain mammalian proteins that activate small GTPases and regulate actin dynamics. The neuronal RhoGEF Kalirin, a central regulator of cytoskeletal dynamics, contains a Sec14 domain (Kal) followed by multiple spectrin-like repeats and catalytic domains. Previous studies demonstrated that Kalirin lacking its Sec14 domain fails to maintain cell morphology or dendritic spine length, yet whether and how Kal interacts with lipids remain unknown. Here, we report the structural and biochemical characterization of Kal. Kal adopts a closed conformation, sealing off the canonical ligand entry site, and instead employs a surface groove to bind a limited set of lysophospholipids. The low-affinity interactions of Kal with lysolipids are expected to serve as a general model for the regulation of Rho signaling by other Sec14-containing Rho activators.
疏水性配体进入独立 Sec14 结构域蛋白的封闭疏水性口袋的门控进入通常将脂质代谢与膜运输联系起来。类似的结构域存在于激活小 GTP 酶并调节肌动蛋白动力学的多结构域哺乳动物蛋白中。神经元 RhoGEF Kalirin 是细胞骨架动力学的中央调节剂，包含一个 Sec14 结构域（Kal），其后是多个 spectrin 样重复和催化结构域。先前的研究表明，缺乏 Sec14 结构域的 Kalirin 无法维持细胞形态或树突棘长度，但 Kalirin 是否以及如何与脂质相互作用仍不清楚。在这里，我们报告了 Kal 的结构和生化特性。Kal 采用封闭构象，封闭了典型的配体进入位点，而是利用表面凹槽来结合有限数量的溶血磷脂。Kal 与溶血磷脂的低亲和力相互作用有望成为其他含有 Sec14 的 Rho 激活剂调节 Rho 信号的一般模型。
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