Structure of the human protein kinase MPSK1 reveals an atypical activation loop architecture.

Structure
Jeyanthy EswaranStefan Knapp

Abstract

The activation segment of protein kinases is structurally highly conserved and central to regulation of kinase activation. Here we report an atypical activation segment architecture in human MPSK1 comprising a beta sheet and a large alpha-helical insertion. Sequence comparisons suggested that similar activation segments exist in all members of the MPSK1 family and in MAST kinases. The consequence of this nonclassical activation segment on substrate recognition was studied using peptide library screens that revealed a preferred substrate sequence of X-X-P/V/I-phi-H/Y-T*-N/G-X-X-X (phi is an aliphatic residue). In addition, we identified the GTPase DRG1 as an MPSK1 interaction partner and specific substrate. The interaction domain in DRG1 was mapped to the N terminus, leading to recruitment and phosphorylation at Thr100 within the GTPase domain. The presented data reveal an atypical kinase structural motif and suggest a role of MPSK1 regulating DRG1, a GTPase involved in regulation of cellular growth.

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Citations

Apr 10, 2012·Annual Review of Biochemistry·Jane A EndicottLouise N Johnson
Sep 25, 2012·Nucleic Acids Research·Sandrea M FrancisBertrand Séraphin
Feb 9, 2016·Structure·Fiona J SorrellStefan Knapp
May 29, 2013·The FEBS Journal·Isabel Pérez-ArellanoJerónimo Bravo
Mar 26, 2010·Archiv der Pharmazie·Matthias RabillerDaniel Rauh
Jul 15, 2015·ACS Chemical Biology·Leila T AlexanderStefan Knapp
Jan 21, 2014·The Biochemical Journal·Apirat ChaikuadSusanne Müller
Oct 27, 2009·Biochimica Et Biophysica Acta·Jeyanthy Eswaran, Stefan Knapp
Apr 16, 2016·ACS Chemical Biology·Feiyang LiuQingsong Liu
Mar 16, 2017·Scientific Reports·Juanjuan LiuXin Zhang
Oct 3, 2019·International Journal of Molecular Sciences·Junjun WangXin Zhang
Apr 13, 2019·International Journal of Molecular Sciences·Junjun WangXin Zhang
Sep 15, 2018·ChemistryOpen·Naomi OhbayashiMikako Shirouzu
Nov 28, 2008·Journal of Medicinal Chemistry·Paul BamboroughKlaus Schneider
Mar 19, 2020·ACS Medicinal Chemistry Letters·Carrow WellsAlison D Axtman

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Datasets Mentioned

BETA
gi4505837

Methods Mentioned

BETA
myristoylation
GTPase
two-hybrid
pull-down
peptide array
ion-exchange chromatography
gel filtration
ELISA

Software Mentioned

XtalView
Phaser
Coot
Mascot
HMMer
Xfit
SSPro

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