Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association

Nature Communications
Onisha PatelIsabelle S Lucet

Abstract

The mammalian pseudokinase SgK223, and its structurally related homologue SgK269, are oncogenic scaffolds that nucleate the assembly of specific signalling complexes and regulate tyrosine kinase signalling. Both SgK223 and SgK269 form homo- and hetero-oligomers, a mechanism that underpins a diversity of signalling outputs. However, mechanistic insights into SgK223 and SgK269 homo- and heterotypic association are lacking. Here we present the crystal structure of SgK223 pseudokinase domain and its adjacent N- and C-terminal helices. The structure reveals how the N- and C-regulatory helices engage in a novel fold to mediate the assembly of a high-affinity dimer. In addition, we identified regulatory interfaces on the pseudokinase domain required for the self-assembly of large open-ended oligomers. This study highlights the diversity in how the kinase fold mediates non-catalytic functions and provides mechanistic insights into how the assembly of these two oncogenic scaffolds is achieved in order to regulate signalling output.

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Citations

Mar 10, 2019·Nature Reviews. Drug Discovery·Jennifer E Kung, Natalia Jura
Jul 18, 2019·Proceedings of the National Academy of Sciences of the United States of America·Mitchell L LopezNatalia Jura
Oct 11, 2019·The FEBS Journal·Onisha PatelIsabelle S Lucet
Apr 25, 2019·Science Signaling·Annie KwonNatarajan Kannan
Aug 15, 2019·Science Signaling·António J M RibeiroPatrick A Eyers
Dec 6, 2018·Biochemical Society Transactions·Amy L Stiegler, Titus J Boggon
Jul 4, 2020·Molecular Cell·Joshua B SheetzMark A Lemmon
Sep 4, 2018·Structure·Amy L Stiegler, Titus J Boggon
Apr 26, 2021·The Journal of Biological Chemistry·Peter D Mace, James M Murphy

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Methods Mentioned

BETA
size-elution chromatography
X-ray
thermal shift
immunoprecipitation
co-immunoprecipitation
co-IP
size exclusion chromatography
PCR
gel filtration
sizing exclusion chromatography

Software Mentioned

CCP4
TScratch
SEDNTERP
BP3
ABS
COOT
PHENIX
XDS
Scatterbrain
PyMOL

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