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Engineering Pak1 Allosteric Switches

Research output: Contribution to journalLetter

Onur Dagliyan, Andrei V. Karginov, Sho Yagishita, Madeline E. Gale, Hui Wang, Celine Dermardirossian, Claire M. Wells, Nikolay V. Dokholyan, Haruo Kasai, Klaus M. Hahn

Original languageEnglish
Pages (from-to)1257-1262
Number of pages6
JournalACS synthetic biology
Volume6
Issue number7
Early online date3 Apr 2017
DOIs
Publication statusPublished - 21 Jul 2017

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Abstract

P21-activated kinases (PAKs) are important regulators of cell motility and morphology. It has been challenging to interrogate their functions because cells adapt to genetic manipulation of PAK, and because inhibitors act on multiple PAK isoforms. Here we describe genetically encoded PAK1 analogues that can be selectively activated by the membrane-permeable small molecule rapamycin. An engineered domain inserted away from the active site responds to rapamycin to allosterically control activity of the PAK1 isoform. To examine the mechanism of rapamycin-induced PAK1 activation, we used molecular dynamics with graph theory to predict amino acids involved in allosteric communication with the active site. This analysis revealed allosteric pathways that were exploited to generate kinase switches. Activation of PAK1 resulted in transient cell spreading in metastatic breast cancer cells, and long-term dendritic spine enlargement in mouse hippocampal CA1 neurons.

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