@article{b5c399b210ba4a8892a5782e333eedb4,
title = "Ndr/Lats Kinases Bind Specific Mob-Family Coactivators through a Conserved and Modular Interface",
abstract = "Ndr/Lats kinases bind Mob coactivator proteins to form complexes that are essential and evolutionarily conserved components of {"}Hippo{"} signaling pathways, which control cell proliferation and morphogenesis in eukaryotes. All Ndr/Lats kinases have a characteristic N-terminal regulatory (NTR) region that binds a specific Mob cofactor: Lats kinases associate with Mob1 proteins, and Ndr kinases associate with Mob2 proteins. To better understand the significance of the association of Mob protein with Ndr/Lats kinases and selective binding of Ndr and Lats to distinct Mob cofactors, we determined crystal structures of Saccharomyces cerevisiae Cbk1NTR-Mob2 and Dbf2NTR-Mob1 and experimentally assessed determinants of Mob cofactor binding and specificity. This allowed a significant improvement in the previously determined structure of Cbk1 kinase bound to Mob2, presently the only crystallographic model of a full length Ndr/Lats kinase complexed with a Mob cofactor. Our analysis indicates that the Ndr/LatsNTR-Mob interface provides a distinctive kinase regulation mechanism, in which the Mob cofactor organizes the Ndr/Lats NTR to interact with the AGC kinase C-terminal hydrophobic motif (HM), which is involved in allosteric regulation. The Mob-organized NTR appears to mediate association of the HM with an allosteric site on the N-terminal kinase lobe. We also found that Cbk1 and Dbf2 associated specifically with Mob2 and Mob1, respectively. Alteration of residues in the Cbk1 NTR allows association of the noncognate Mob cofactor, indicating that cofactor specificity is restricted by discrete sites rather than being broadly distributed. Overall, our analysis provides a new picture of the functional role of Mob association and indicates that the Ndr/LatsNTR-Mob interface is largely a common structural platform that mediates kinase-cofactor binding.",
author = "Parker, {Benjamin W.} and Gergo Gogl and M{\'o}nika B{\'a}lint and Csaba Het{\'e}nyi and Attila Rem{\'e}nyi and Weiss, {Eric L.}",
note = "Funding Information: This work was supported by the National Institutes of Health (Grant 5R01GM084223-08) and by the Hungarian National Research, Development and Innovation Office (NN 114309 and KKP 126963). The work of C.H. and M.B. was supported by the Hungarian National Research, Development and Innovation Office (K123836) and the J{\'a}nos Bolyai Research Scholarship of the Hungarian Academy of Sciences. The authors acknowledge the grant of computer time from the Governmental Information Technology Development Agency (KIF{\"U}) of Hungary. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: The authors thank Kyle Schneider for the Cbk1–Mob2 expression plasmids. The authors thank Jonathan Hsu for the bicistronic plasmid backbone. The authors acknowledge a grant of computer time from the CSCS Swiss National Supercomputing Centre and the NIIF Hungarian National Information Infrastructure Development Institute. The authors acknowledge staff and instrumentation support from the Structural Biology Facility at Northwestern University, the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, and NCI CCSG P30 CA060553. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. Use of LS-CAT Sector 21 was supported by the Michigan Economic Development Corp. and the Michigan Technology Tri-Corridor (Grant 085P1000817). Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",
year = "2020",
month = may,
day = "5",
doi = "10.1021/acs.biochem.9b01096",
language = "English (US)",
volume = "59",
pages = "1688--1700",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "17",
}