Engineering Pak1 Allosteric Switches

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1257-1262
Number of pages6
JournalACS Synthetic Biology
Volume6
Issue number7
DOIs
StatePublished - Jul 21 2017

Fingerprint

p21-Activated Kinases
Sirolimus
Chemical activation
Switches
Graph theory
Catalytic Domain
Protein Isoforms
Neurons
Molecular dynamics
Amino acids
Dendritic Spines
Cells
Molecular Dynamics Simulation
Membranes
Molecules
Cell Movement
Communication
Phosphotransferases
Breast Neoplasms
Amino Acids

All Science Journal Classification (ASJC) codes

  • Biomedical Engineering
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

Cite this

Dagliyan, O., Karginov, A. V., Yagishita, S., Gale, M. E., Wang, H., Dermardirossian, C., ... Hahn, K. M. (2017). Engineering Pak1 Allosteric Switches. ACS Synthetic Biology, 6(7), 1257-1262. https://doi.org/10.1021/acssynbio.6b00359
Dagliyan, Onur ; Karginov, Andrei V. ; Yagishita, Sho ; Gale, Madeline E. ; Wang, Hui ; Dermardirossian, Celine ; Wells, Claire M. ; Dokholyan, Nikolay V. ; Kasai, Haruo ; Hahn, Klaus M. / Engineering Pak1 Allosteric Switches. In: ACS Synthetic Biology. 2017 ; Vol. 6, No. 7. pp. 1257-1262.
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Dagliyan, O, Karginov, AV, Yagishita, S, Gale, ME, Wang, H, Dermardirossian, C, Wells, CM, Dokholyan, NV, Kasai, H & Hahn, KM 2017, 'Engineering Pak1 Allosteric Switches', ACS Synthetic Biology, vol. 6, no. 7, pp. 1257-1262. https://doi.org/10.1021/acssynbio.6b00359

Engineering Pak1 Allosteric Switches. / Dagliyan, Onur; Karginov, Andrei V.; Yagishita, Sho; Gale, Madeline E.; Wang, Hui; Dermardirossian, Celine; Wells, Claire M.; Dokholyan, Nikolay V.; Kasai, Haruo; Hahn, Klaus M.

In: ACS Synthetic Biology, Vol. 6, No. 7, 21.07.2017, p. 1257-1262.

Research output: Contribution to journalArticle

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AU - Yagishita, Sho

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AU - Dokholyan, Nikolay V.

AU - Kasai, Haruo

AU - Hahn, Klaus M.

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Dagliyan O, Karginov AV, Yagishita S, Gale ME, Wang H, Dermardirossian C et al. Engineering Pak1 Allosteric Switches. ACS Synthetic Biology. 2017 Jul 21;6(7):1257-1262. https://doi.org/10.1021/acssynbio.6b00359