Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the role of Thr-286 autophosphorylation in the autoregulation of Ca2+/calmodulin-dependent protein kinase II. Using site-directed mutagenesis, we have substituted alanine or serine for Thr-286, or isoleucine for Arg-283, in the 50-kDa subunit of the kinase and expressed each protein in bacteria. Activation and autophosphorylation of all four enzymes were stringently dependent on Ca2+/calmodulin, indicating that neither Arg-283 nor Thr-286 is an absolute requirement for the pseudosubstrate inhibition of the enzyme. Autophosphorylation of the Ile-283 or Ala-286 enzyme generated little, if any, Ca2+/calmodulin-independent kinase activity, unlike the parent (Thr-286) or Ser-286 enzyme. The enzymes expressed in bacteria are predominantly monomeric, indicating that the generation of Ca2+/calmodulin-independent activity does not require the cooperative interactions of subunits normally present in the brain holoenzyme.
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PMID:Mutagenesis of Thr-286 in monomeric Ca2+/calmodulin-dependent protein kinase II eliminates Ca2+/calmodulin-independent activity. 215 38

Branched chain aminotransferase (BCAT) catalyzes the transamination of the essential branched chain amino acids (leucine, isoleucine and valine) with alpha-ketoglutarate. BCAT exists in two isoforms: one cytosolic (BCATc), mainly expressed in the nervous system, and the other mitochondrial (BCATm), present in a greater number of tissues. We previously showed that BCATc mRNA and protein expression in the dorsal lateral geniculate nucleus of the thalamus is up-regulated by exogenous administration of brain-derived neurotrophic factor (BDNF) following lesion of the visual cortex in newborn rats. Here, we analyzed the expression of BCATc mRNA in the brain of transgenic mice overexpressing the rat BDNF cDNA under the control of the alpha-calcium/calmodulin-dependent kinase II (alphaCaMKII) promoter. In these animals, BDNF is overexpressed in the telencephalon starting from the second postnatal week. RT-PCR and in situ hybridization experiments showed that BCATc mRNA is overexpressed in restricted regions of the cerebral cortex (parietal area) and hippocampus (hilus and CA3 pyramidal cell layer) of adult BDNF transgenic mice respect to wild-type animals. These differences between wt and BDNF mice were not detected in animals of 1 week of age. These results demonstrate that the expression of the BCATc gene in the brain is specifically regulated by BDNF in a time- and region-dependent fashion.
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PMID:Cytosolic branched chain aminotransferase (BCATc) mRNA is up-regulated in restricted brain areas of BDNF transgenic mice. 1682 66

Purkinje cell protein 4-like 1 (Pcp4l1) is a small neuronal IQ motif protein closely related to the calmodulin-binding protein Pcp4/PEP-19. PEP-19 interacts with calmodulin via its IQ motif to inhibit calmodulin-dependent enzymes and we hypothesized Pcp4l1 would have similar properties. Surprisingly, full-length Pcp4l1 does not interact with calmodulin in yeast two-hybrid or pulldown experiments yet a synthetic peptide constituting only the IQ motif of Pcp4l1 binds calmodulin and inhibits calmodulin-dependent kinase II. A nine-residue glutamic acid-rich sequence in Pcp4l1 confers these unexpected properties. This element lies outside the IQ motif and its deletion or exchange with the homologous region of PEP-19 restores calmodulin binding. Conversion of a single isoleucine (Ile36) within this motif to phenylalanine, the residue present in PEP-19, imparts calmodulin binding onto Pcp4l1. Moreover, only aromatic amino acid substitutions at position 36 in Pcp4l1 allow binding. Thus, despite their sequence similarities PEP-19 and Pcp4l1 have distinct properties with the latter harboring an element that can functionally suppress an IQ motif. We speculate Pcp4l1 may be a latent calmodulin inhibitor regulated by post-translational modification and/or co-factor interactions.
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PMID:Pcp4l1 contains an auto-inhibitory element that prevents its IQ motif from binding to calmodulin. 2245 99

The L-type voltage-gated calcium channel Cav1.2 and the calcium-activated CaM kinase cascade both regulate excitation transcription coupling in the brain. CaM kinase is known to associate with the C terminus of Cav1.2 in a region called the PreIQ-IQ domain, which also binds multiple calmodulin molecules. Here we identify and characterize a second CaMKII binding site in the N terminus of Cav1.2 that is formed by a stretch of four amino residues (cysteine-isoleucine-serine-isoleucine) and which regulates channel expression and function. By using live cell imaging of tsA-201 cells we show that GFP fusion constructs of the CaMKII binding region, termed N2B-II co-localize with mCherry-CaMKII. Mutating CISI to AAAA ablates binding to and colocalization with CaMKII. Cav1.2-AAAA channels show reduced cell surface expression in tsA-201 cells, but interestingly, display an increase in channel function that offsets the trafficking deficit. Altogether our data reveal that the proximal N terminus of Cav1.2 contains a CaMKII binding region which contributes to channel surface expression and function.
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PMID:The Cav1.2 N terminus contains a CaM kinase site that modulates channel trafficking and function. 2486 38