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冷冻电镜结构的 Hippo 信号整合因子人 STRIPAK。

Cryo-EM structure of the Hippo signaling integrator human STRIPAK.

机构信息

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

出版信息

Nat Struct Mol Biol. 2021 Mar;28(3):290-299. doi: 10.1038/s41594-021-00564-y. Epub 2021 Feb 25.

DOI:10.1038/s41594-021-00564-y
PMID:33633399
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8315899/
Abstract

The striatin-interacting phosphatase and kinase (STRIPAK) complex is a large, multisubunit protein phosphatase 2A (PP2A) assembly that integrates diverse cellular signals in the Hippo pathway to regulate cell proliferation and survival. The architecture and assembly mechanism of this critical complex are poorly understood. Using cryo-EM, we determine the structure of the human STRIPAK core comprising PP2AA, PP2AC, STRN3, STRIP1, and MOB4 at 3.2-Å resolution. Unlike the canonical trimeric PP2A holoenzyme, STRIPAK contains four copies of STRN3 and one copy of each the PP2AA-C heterodimer, STRIP1, and MOB4. The STRN3 coiled-coil domains form an elongated homotetrameric scaffold that links the complex together. An inositol hexakisphosphate (IP) is identified as a structural cofactor of STRIP1. Mutations of key residues at subunit interfaces disrupt the integrity of STRIPAK, causing aberrant Hippo pathway activation. Thus, STRIPAK is established as a noncanonical PP2A complex with four copies of regulatory STRN3 for enhanced signal integration.

摘要

STRIPAK 复合物是一个大型的多亚基蛋白磷酸酶 2A（PP2A）组装体，它整合 Hippo 通路中的各种细胞信号，以调节细胞增殖和存活。该关键复合物的结构和组装机制了解甚少。我们使用冷冻电镜，以 3.2-Å 的分辨率确定了包含 PP2AA、PP2AC、STRN3、STRIP1 和 MOB4 的人 STRIPAK 核心的结构。与典型的三聚体 PP2A 全酶不同，STRIPAK 包含四个 STRN3 拷贝和一个 PP2AA-C 异源二聚体、STRIP1 和 MOB4 拷贝。STRN3 卷曲螺旋结构域形成一个长的同源四聚体支架，将复合物连接在一起。鉴定出肌醇六磷酸（IP）是 STRIP1 的结构辅助因子。亚基界面关键残基的突变破坏了 STRIPAK 的完整性，导致 Hippo 通路异常激活。因此，STRIPAK 被确定为一种非典型的 PP2A 复合物，具有四个调节 STRN3 拷贝，用于增强信号整合。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13de/8315899/9d34a3ff1d9a/nihms-1722364-f0005.jpg
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