Calcium-binding protein 39 facilitates molecular interaction between Ste20p proline alanine-rich kinase and oxidative stress response 1 monomers
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The three-model screen
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Biochemistry study of calcium-binding protein 39 and SPAK kinase dimerization; molecular signalling.
It investigates molecular kinase interactions, not research itself.
Molecular cell biology of SPAK/OSR1 kinase dimers and Cab39; domain biochemistry.
Abstract
X-ray crystallography of the catalytic domain of oxidative stress response 1 (OSR1) has provided evidence for dimerization and domain swapping. However, the functional significance of dimer formation or domain swapping has yet to be addressed. In this study, we used nine glutamine residues to link the carboxyl end of one SPAK (related Ste20 kinase) monomer to the amino end of another SPAK monomer to assess the role of kinase monomers versus dimers in Na-K-2Cl cotransporter 1 (NKCC1) activation. Transport studies in Xenopus laevis oocytes show that forcing dimerization of two wild-type SPAK molecules results in cotransporter activation when calcium-binding protein 39 (Cab39) is coexpressed, indicating that the presence of Cab39 can bypass the upstream phosphorylation requirement of SPAK normally associated with kinase activation. We determined that monomers are the functional units of the kinase as concatamers consisting of an active and various inactive monomers were still functional. Furthermore, we found that two different nonfunctional SPAK mutants could be linked together in a concatamer and activated, presumably by domain swapping, indicating that dimerization and domain swapping are both important components of kinase activation. Finally, we demonstrate rescue of a nonfunctional SPAK mutant by domain swapping with wild-type OSR1, indicating that heterodimers of the two Ste20-related kinases are possible and therefore potentially relevant to the regulation of NKCC1 activity.
Stored with the screening record, where it is evidence for the labels above.
The record
- Venue
- American Journal of Physiology-Cell Physiology
- Topic
- Ion Transport and Channel Regulation
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- University of Saskatchewan
- Funders
- National Institute of General Medical Sciences
- Keywords
- KinaseAlanineProtein kinase domainChemistryBiochemistryDimerSerineMonomerMutantPhosphorylationProtein kinase ACell biologyWild typeProtein subunitAmino acidBiologyGene
- Has abstract in OpenAlex
- yes