Proteomics

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Biophysical basis of cellular multi-specificity encoded in a model molecular switch


ABSTRACT: Molecular switches are central to many cellular networks, enabling signal processing via interactions with molecules that write, erase, or read the active state of the switch. One switch protein can independently regulate distinct processes, but the molecular mechanisms enabling this functional multi-specificity remain unclear. Here we integrate system-scale cellular and biophysical measurements to study how a paradigm switch, the small GTPase Ran/Gsp1, achieves its functional multi-specificity. We make targeted point mutations to individual interactions of Ran/Gsp1 and show through genetic and physical interaction mapping that Ran/Gsp1 interface perturbations have widespread cellular consequences that cluster by biological processes but, unexpectedly, not by the targeted interactions. Instead, the cellular consequences of the interface mutations group by their biophysical effects on kinetic parameters of the GTPase switch cycle, and cycle kinetics are allosterically tuned by distal interface mutations. We propose that the functional multi-specificity of Ran/Gsp1 is explained by a differential sensitivity of biological processes to different kinetic parameters of the Gsp1 switch cycle, and that Gsp1 switch readers binding to the sites of distal mutations can also act as allosteric writers and erasers of the switch cycle. Similar mechanisms may underlie biological regulation by other GTPases and biological switches in general.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Danielle Swaney  

LAB HEAD: Nevan Krogan

PROVIDER: PXD016338 | Pride | 2020-05-18

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
ExperimentalDesign.xlsx Xlsx
SGD_20150113_orf_trans_all.fasta Fasta
mqpar.xml Xml
qx009416.raw Raw
qx009418.raw Raw
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