TY - JOUR
T1 - Cryo-EM structure of the Hippo signaling integrator human STRIPAK
AU - Jeong, Byung Cheon
AU - Bae, Sung Jun
AU - Ni, Lisheng
AU - Zhang, Xuewu
AU - Bai, Xiao chen
AU - Luo, Xuelian
N1 - Funding Information:
We thank H. Yu for helpful discussion. We thank S. Liu for assistance with mutant analysis. Single-particle cryo-EM data were collected at the University of Texas Southwestern Medical Center (UTSW) Cryo-Electron Microscopy Facility, which is funded by a Cancer Prevention and Research Institute of Texas (CPRIT) Core Facility Support Award (Grant no. RP170644). We thank D. Nicastro for facility access and data acquisition. This study is supported in part by grants from the National Institutes of Health (CA220283 to X.Z.; GM132275 to X.L.), and grants from the Welch Foundation (I-1702 to X.Z.; I-1944 to X.-c.B.; I-1932 to X.L.). X.Z. and X.-c.B. are Virginia Murchison Linthicum Scholars in Medical Research at UTSW.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/3
Y1 - 2021/3
N2 - 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 (IP6) 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.
AB - 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 (IP6) 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.
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U2 - 10.1038/s41594-021-00564-y
DO - 10.1038/s41594-021-00564-y
M3 - Article
C2 - 33633399
AN - SCOPUS:85101740458
SN - 1545-9993
VL - 28
SP - 290
EP - 299
JO - Nature Structural Biology
JF - Nature Structural Biology
IS - 3
ER -