Rewiring MAP kinase pathways using alternative scaffold assembly mechanisms.
How scaffold proteins control information flow in signaling pathways is poorly understood: Do they simply tether components, or do they precisely orient and activate them? We found that the yeast mitogen-activated protein (MAP) kinase scaffold Ste5 is tolerant to major stereochemical perturbations; heterologous protein interactions could functionally replace native kinase recruitment interactions, indicating that simple tethering is largely sufficient for scaffold-mediated signaling. Moreover, by engineering a scaffold that tethers a unique kinase set, we could create a synthetic MAP kinase pathway with non-natural input-output properties. These findings demonstrate that scaffolds are highly flexible organizing factors that can facilitate pathway evolution and engineering.
Park
Sang-Hyun
SH
Department of Cellular and Molecular Pharmacology and Department of Biochemistry and Biophysics, University of California, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
Zarrinpar
Ali
A
Lim
Wendell A
WA
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009994:Osmolar Concentration; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C048632:MF(ALPHA)1 protein, S cerevisiae; D008565:Membrane Proteins; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; C459787:SHO1 protein, S cerevisiae; C080321:STE5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; C075580:FUS3 protein, S cerevisiae; C088589:HOG1 protein, S cerevisiae; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C067018:Ste11 protein, S cerevisiae; D020929:Mitogen-Activated Protein Kinase Kinases; C089356:PBS2 protein, S cerevisiae; C119844:STE7 protein, S cerevisiae