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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 and Elkins, Jonathan M. 2013. Structural insights into the activation of MST3 by MO25. Biochemical and Biophysical Research Communications 431 (3) , pp. 604-609. 10.1016/j.bbrc.2012.12.113

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Protein kinase; LKB1; Signal transduction; Protein structure and STE20
Publisher: Elsevier
ISSN: 0006-291X
Funders: MRC
Date of First Compliant Deposit: 27 January 2017
Last Modified: 04 Jun 2017 09:35
URI: http://orca.cf.ac.uk/id/eprint/97275

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