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Nat Commun. 2017 Oct 27;8(1):1157. doi: 10.1038/s41467-017-01279-9.

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

Author information

1
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. patel.o@wehi.edu.au.
2
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. patel.o@wehi.edu.au.
3
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, 3052, Australia.
4
Australian Synchrotron, Clayton, VIC, 3168, Australia.
5
Department of Biochemistry and Molecular Biology, Level 1, Building 77, Monash University, Clayton, VIC, 3800, Australia.
6
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
7
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
8
Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
9
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. lucet.i@wehi.edu.au.
10
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. lucet.i@wehi.edu.au.

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.

PMID:
29079850
PMCID:
PMC5660093
DOI:
10.1038/s41467-017-01279-9
[Indexed for MEDLINE]
Free PMC Article

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