Engineering Pak1 Allosteric Switches
Year: 2017
Type: article
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.
Source: ACS Synthetic Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Howard Hughes Medical Institute, Ministry of Education, Culture, Sports, Science and Technology, Japan Society for the Promotion of Science, Japan Science and Technology Agency, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Biomedical Imaging and Bioengineering
OpenAlex ID: W2604304370