Structural insights into the activation of MST3 by MO25

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Structural insights into the activation of MST3 by MO25. / Mehellou, Youcef; Alessi, Dario R; Macartney, Thomas J; Szklarz, Marta; Knapp, Stefan; Elkins, Jonathan M.

In: Biochemical and Biophysical Research Communications, Vol. 431, No. 3, 15.02.2013, p. 604-9.

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Mehellou, Youcef ; Alessi, Dario R ; Macartney, Thomas J ; Szklarz, Marta ; Knapp, Stefan ; Elkins, Jonathan M. / Structural insights into the activation of MST3 by MO25. In: Biochemical and Biophysical Research Communications. 2013 ; Vol. 431, No. 3. pp. 604-9.

Bibtex

@article{bceadd125a9a4ddcaf122d27c4097aad,
title = "Structural insights into the activation of MST3 by MO25",
abstract = "The MO25 scaffolding protein operates as critical regulator of a number of STE20 family protein kinases (e.g. MST and SPAK isoforms) as well as pseudokinases (e.g. STRAD isoforms that play a critical role in activating the LKB1 tumour suppressor). To better understand how MO25 interacts and stimulates the activity of STE20 protein kinases, we determined the crystal structure of MST3 catalytic domain (residues 19-289) in complex with full length MO25β. The structure reveals an intricate web of interactions between MST3 and MO25β that function to stabilise the kinase domain in a closed, active, conformation even in the absence of ATP or an ATP-mimetic inhibitor. The binding mode of MO25β is reminiscent of the mechanism by which MO25α interacts with the pseudokinase STRADα. In particular we identified interface residues Tyr223 of MO25β and Glu58 and Ile71 of MST3 that when mutated prevent activation of MST3 by MO25β. These data provide molecular understanding of the mechanism by which MO25 isoforms regulates the activity of STE20 family protein kinases.",
author = "Youcef Mehellou and Alessi, {Dario R} and Macartney, {Thomas J} and Marta Szklarz and Stefan Knapp and Elkins, {Jonathan M}",
note = "Copyright {\textcopyright} 2013 Elsevier Inc. All rights reserved.",
year = "2013",
month = feb,
day = "15",
doi = "10.1016/j.bbrc.2012.12.113",
language = "English",
volume = "431",
pages = "604--9",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Elsevier",
number = "3",

}

RIS

TY - JOUR

T1 - Structural insights into the activation of MST3 by MO25

AU - Mehellou, Youcef

AU - Alessi, Dario R

AU - Macartney, Thomas J

AU - Szklarz, Marta

AU - Knapp, Stefan

AU - Elkins, Jonathan M

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

PY - 2013/2/15

Y1 - 2013/2/15

N2 - The MO25 scaffolding protein operates as critical regulator of a number of STE20 family protein kinases (e.g. MST and SPAK isoforms) as well as pseudokinases (e.g. STRAD isoforms that play a critical role in activating the LKB1 tumour suppressor). To better understand how MO25 interacts and stimulates the activity of STE20 protein kinases, we determined the crystal structure of MST3 catalytic domain (residues 19-289) in complex with full length MO25β. The structure reveals an intricate web of interactions between MST3 and MO25β that function to stabilise the kinase domain in a closed, active, conformation even in the absence of ATP or an ATP-mimetic inhibitor. The binding mode of MO25β is reminiscent of the mechanism by which MO25α interacts with the pseudokinase STRADα. In particular we identified interface residues Tyr223 of MO25β and Glu58 and Ile71 of MST3 that when mutated prevent activation of MST3 by MO25β. These data provide molecular understanding of the mechanism by which MO25 isoforms regulates the activity of STE20 family protein kinases.

AB - The MO25 scaffolding protein operates as critical regulator of a number of STE20 family protein kinases (e.g. MST and SPAK isoforms) as well as pseudokinases (e.g. STRAD isoforms that play a critical role in activating the LKB1 tumour suppressor). To better understand how MO25 interacts and stimulates the activity of STE20 protein kinases, we determined the crystal structure of MST3 catalytic domain (residues 19-289) in complex with full length MO25β. The structure reveals an intricate web of interactions between MST3 and MO25β that function to stabilise the kinase domain in a closed, active, conformation even in the absence of ATP or an ATP-mimetic inhibitor. The binding mode of MO25β is reminiscent of the mechanism by which MO25α interacts with the pseudokinase STRADα. In particular we identified interface residues Tyr223 of MO25β and Glu58 and Ile71 of MST3 that when mutated prevent activation of MST3 by MO25β. These data provide molecular understanding of the mechanism by which MO25 isoforms regulates the activity of STE20 family protein kinases.

U2 - 10.1016/j.bbrc.2012.12.113

DO - 10.1016/j.bbrc.2012.12.113

M3 - Article

C2 - 23296203

VL - 431

SP - 604

EP - 609

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 3

ER -