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

Onisha Patel, Michael D.W. Griffin, Santosh Panjikar, Weiwen Dai, Xiuquan Ma, Howard Chan, Celine Zheng, Ashleigh Kropp, James M. Murphy, Roger J. Daly, Isabelle S. Lucet

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Article number1157
Number of pages15
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

Keywords

  • cancer
  • kinases
  • x-ray crystallography

Cite this

Patel, Onisha ; Griffin, Michael D.W. ; Panjikar, Santosh ; Dai, Weiwen ; Ma, Xiuquan ; Chan, Howard ; Zheng, Celine ; Kropp, Ashleigh ; Murphy, James M. ; Daly, Roger J. ; Lucet, Isabelle S. / Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association. In: Nature Communications. 2017 ; Vol. 8, No. 1.
@article{01e511d0037b49289a9e7f26324c8f8a,
title = "Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association",
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.",
keywords = "cancer, kinases, x-ray crystallography",
author = "Onisha Patel and Griffin, {Michael D.W.} and Santosh Panjikar and Weiwen Dai and Xiuquan Ma and Howard Chan and Celine Zheng and Ashleigh Kropp and Murphy, {James M.} and Daly, {Roger J.} and Lucet, {Isabelle S.}",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41467-017-01279-9",
language = "English",
volume = "8",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association. / Patel, Onisha; Griffin, Michael D.W.; Panjikar, Santosh; Dai, Weiwen; Ma, Xiuquan; Chan, Howard; Zheng, Celine; Kropp, Ashleigh; Murphy, James M.; Daly, Roger J.; Lucet, Isabelle S.

In: Nature Communications, Vol. 8, No. 1, 1157, 01.12.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association

AU - Patel, Onisha

AU - Griffin, Michael D.W.

AU - Panjikar, Santosh

AU - Dai, Weiwen

AU - Ma, Xiuquan

AU - Chan, Howard

AU - Zheng, Celine

AU - Kropp, Ashleigh

AU - Murphy, James M.

AU - Daly, Roger J.

AU - Lucet, Isabelle S.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - cancer

KW - kinases

KW - x-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=85032483743&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-01279-9

DO - 10.1038/s41467-017-01279-9

M3 - Article

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 1157

ER -