Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada.
Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20346-51. doi: 10.1073/pnas.1009008107. Epub 2010 Nov 5.
Phosphatidylinositol 3,4,5-triphosphate (PIP3) plays a key role in neuronal polarization and axon formation. PIP3-containing vesicles are transported to axon tips by the kinesin KIF13B via an adaptor protein, centaurin α1 (CENTA1). KIF13B interacts with CENTA1 through its forkhead-associated (FHA) domain. We solved the crystal structures of CENTA1 in ligand-free, KIF13B-FHA domain-bound, and PIP3 head group (IP4)-bound conformations, and the CENTA1/KIF13B-FHA/IP4 ternary complex. The first pleckstrin homology (PH) domain of CENTA1 specifically binds to PIP3, while the second binds to both PIP3 and phosphatidylinositol 3,4-biphosphate (PI(3,4)P(2)). The FHA domain of KIF13B interacts with the PH1 domain of one CENTA1 molecule and the ArfGAP domain of a second CENTA1 molecule in a threonine phosphorylation-independent fashion. We propose that full-length KIF13B and CENTA1 form heterotetramers that can bind four phosphoinositide molecules in the vesicle and transport it along the microtubule.
磷脂酰肌醇 3,4,5-三磷酸(PIP3)在神经元极化和轴突形成中起着关键作用。通过衔接蛋白 centaurin α1(CENTA1),含有 PIP3 的囊泡被运送到轴突末端的驱动蛋白 KIF13B。KIF13B 通过其与叉头相关(FHA)结构域与 CENTA1 相互作用。我们解析了无配体、KIF13B-FHA 结构域结合、以及 PIP3 头部基团(IP4)结合构象的 CENTA1 的晶体结构,以及 CENTA1/KIF13B-FHA/IP4 三元复合物的晶体结构。CENTA1 的第一个pleckstrin 同源(PH)结构域特异性结合 PIP3,而第二个 PH 结构域同时结合 PIP3 和磷脂酰肌醇 3,4-二磷酸(PI(3,4)P(2))。KIF13B 的 FHA 结构域以一种不依赖于苏氨酸磷酸化的方式与一个 CENTA1 分子的 PH1 结构域和第二个 CENTA1 分子的 ArfGAP 结构域相互作用。我们提出全长 KIF13B 和 CENTA1 形成异四聚体,能够在囊泡中结合四个磷酸肌醇分子,并沿着微管运输囊泡。