Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform.

Yan, Dong

Jin, Yishi

United States

2015-09-16T21:39:01Z

2012-11-08

MAPKKK dual leucine zipper-bearing kinases (DLKs) are regulators of synaptic development and axon regeneration. The mechanisms underlying their activation are not fully understood. Here, we show that C. elegans DLK-1 is activated by a Ca(2+)-dependent switch from inactive heteromeric to active homomeric protein complexes. We identify a DLK-1 isoform, DLK-1S, that shares identical kinase and leucine zipper domains with the previously described long isoform DLK-1L but acts to inhibit DLK-1 function by binding to DLK-1L. The switch between homo- or heteromeric DLK-1 complexes is influenced by Ca(2+) concentration. A conserved hexapeptide in the DLK-1L C terminus is essential for DLK-1 activity and is required for Ca(2+) regulation. The mammalian DLK-1 homolog MAP3K13 contains an identical C-terminal hexapeptide and can functionally complement dlk-1 mutants, suggesting that the DLK activation mechanism is conserved. The DLK activation mechanism is ideally suited for rapid and spatially controlled signal transduction in response to axonal injury and synaptic activity.

http://www.ncbi.nlm.nih.gov/pubmed/23141066

S0896-6273(12)00929-4

1097-4199

https://hdl.handle.net/10161/10618

eng

Elsevier BV

Neuron

10.1016/j.neuron.2012.08.043

Animals

Caenorhabditis elegans

Caenorhabditis elegans Proteins

Calcium

Enzyme Activation

Humans

Isoenzymes

MAP Kinase Kinase Kinases

Mutation

Neural Inhibition

Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform.

Journal article

http://www.ncbi.nlm.nih.gov/pubmed/23141066

534

548

3

Basic Science Departments

Duke

Duke Institute for Brain Sciences

Institutes and Provost's Academic Units

Molecular Genetics and Microbiology

Neurobiology

School of Medicine

University Institutes and Centers

Published

76