Catalytic and regulatory domains of doublecortin kinase-1

Limin Shang, Young Guen Kwon, Sandip Nandy, David S. Lawrence, Arthur M. Edelman

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Abstract

Doublecortin kinase-1 (DCK1) is a newly described multidomain protein kinase with a sequence significantly similar to those of both CaM kinases (CaMKs) and doublecortin, the product of the gene mutated in X-linked lissencephaly/double cortex syndome, a severe developmental disorder of the nervous system. Functional studies have revealed microtubule binding and polymerization activities of the doublecortin domain, yet little is known regarding the enzymatic properties and regulation of the kinase catalytic domain. We have identified and report here notable similarities as well as differences between the catalytic and regulatory properties of DCK1 and those of the CaMKs. Using synthetic peptide substrates modeled on synapsin I, a substrate recognition motif for DCK1 of Hyd-Arg-Arg-X-X-Ser*/Thr*-Hyd was derived. The similarity of this motif to that of CaMKI [Lee, J. C., Kwon, Y.-G., Lawrence, D. S., and Edelman, A. M. (1994) Proc. Natl. Acad. Sci. U.S.A. 91, 6413-6417] is consistent with the 59% level of amino acid sequence similarity between their catalytic domains. DCK1 catalytic activity is enhanced by mutagenic introduction of negative charge at Thr-239, a residue in a position equivalent to that of Thr-177 of CaMKI, the activation loop site for regulation by CaM kinase kinase. Unlike CaMKs, DCK1 is not directly activated by Ca2+-bound CaM. However, truncation of a pseudosubstrate-like sequence in the C-terminus of DCK1 results in an ∼6-fold enhancement of activity. Thus, DCK1 demonstrates the potential to be regulated by relief of autoinhibition in response to signal(s) distinct from Ca2+-bound CaM and potentially by activation loop phosphorylation and to phosphorylate intracellular targets at sites similar to those recognized by CaMK pathways.

Original languageEnglish
Pages (from-to)2185-2194
Number of pages10
JournalBiochemistry
Volume42
Issue number7
DOIs
Publication statusPublished - 2003 Feb 25

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All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Shang, L., Kwon, Y. G., Nandy, S., Lawrence, D. S., & Edelman, A. M. (2003). Catalytic and regulatory domains of doublecortin kinase-1. Biochemistry, 42(7), 2185-2194. https://doi.org/10.1021/bi026913i