| Structural highlights
Function
[KCC1A_RAT] Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK1 signaling cascade and, upon calcium influx, regulates transcription activators activity, cell cycle, hormone production, cell differentiation, actin filament organization and neurite outgrowth. Recognizes the substrate consensus sequence [MVLIF]-x-R-x(2)-[ST]-x(3)-[MVLIF]. Regulates axonal extension and growth cone motility in hippocampal and cerebellar nerve cells. Upon NMDA receptor-mediated Ca(2+) elevation, promotes dendritic growth in hippocampal neurons and is essential in synapses for full long-term potentiation (LTP) and ERK2-dependent translational activation. Downstream of NMDA receptors, promotes the formation of spines and synapses in hippocampal neurons by phosphorylating ARHGEF7/BETAPIX on 'Ser-516', which results in the enhancement of ARHGEF7 activity and activation of RAC1. Promotes neuronal differentiation and neurite outgrowth by activation and phosphorylation of MARK2 on 'Ser-91', 'Ser-92', 'Ser-93' and 'Ser-294'. Promotes nuclear export of HDAC5 and binding to 14-3-3 by phosphorylation of 'Ser-259' and 'Ser-498' in the regulation of muscle cell differentiation (By similarity). Regulates NUMB-mediated endocytosis by phosphorylation of NUMB on 'Ser-275' and 'Ser-294'. Involved in the regulation of basal and estrogen-stimulated migration of medulloblastoma cells through ARHGEF7/BETAPIX phosphorylation (By similarity). Is required for proper activation of cyclin-D1/CDK4 complex during G1 progression in diploid fibroblasts. Plays a role in K(+) and ANG2-mediated regulation of the aldosterone synthase (CYP11B2) to produce aldosterone in the adrenal cortex. Phosphorylates EIF4G3/eIF4GII. In vitro phosphorylates CREB1, ATF1, CFTR, MYL9 and SYN1/synapsin I.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Here we present a novel NMR method for the structure determination of calcium-calmodulin (Ca(2+)-CaM)-peptide complexes from a limited set of experimental restraints. A comparison of solved CaM-peptide structures reveals invariability in CaM's backbone conformation and a structural plasticity in CaM's domain orientation enabled by a flexible linker. Knowing this, the collection and analysis of an extensive set of NOESY spectra is redundant. Although RDCs can define CaM domain orientation in the complex, they lack the translational information required to position the domains on the bound peptide and highlight the necessity of intermolecular NOEs. Here we employ a specific isotope labeling strategy in which the role of methionine in CaM-peptide interactions is exploited to collect these critical NOEs. By (1)H, (13)C-labeling the methyl groups of deuterated methionine against a (2)H, (12)C background, we can acquire a (13)C-edited NOESY characterized by simplified, easily analyzable spectra. Together with measured CaM backbone H(N)-N RDCs and intrapeptide NOE-based distances, these intermolecular NOEs provide restraints for a low temperature torsion-angle dynamics and simulated annealing protocol used to calculate the complex structure. We have applied our method to a CaM complex previously solved through X-ray crystallography: Ca(2+)-CaM bound to the CaM kinase I peptide (PDB code: 1MXE). The resulting structure has a backbone RMSD of 1.6 A to that previously published. We have also used this test complex to investigate the importance of homologous model selection on the calculated outcome. In addition to having application for fast complex structure determination, this method can be used to determine the structures of difficult complexes characterized by chemical shift overlap and broad signals for which the traditional method based on the use of fully (13)C, (15)N-labeled CaM fails.
Fast methionine-based solution structure determination of calcium-calmodulin complexes.,Gifford JL, Ishida H, Vogel HJ J Biomol NMR. 2011 May;50(1):71-81. Epub 2011 Mar 1. PMID:21360154[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sheng M, Thompson MA, Greenberg ME. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science. 1991 Jun 7;252(5011):1427-30. PMID:1646483
- ↑ Sun P, Lou L, Maurer RA. Regulation of activating transcription factor-1 and the cAMP response element-binding protein by Ca2+/calmodulin-dependent protein kinases type I, II, and IV. J Biol Chem. 1996 Feb 9;271(6):3066-73. PMID:8621702
- ↑ Suizu F, Fukuta Y, Ueda K, Iwasaki T, Tokumitsu H, Hosoya H. Characterization of Ca2+/calmodulin-dependent protein kinase I as a myosin II regulatory light chain kinase in vitro and in vivo. Biochem J. 2002 Oct 15;367(Pt 2):335-45. PMID:12081505 doi:10.1042/BJ20020536
- ↑ Wayman GA, Kaech S, Grant WF, Davare M, Impey S, Tokumitsu H, Nozaki N, Banker G, Soderling TR. Regulation of axonal extension and growth cone motility by calmodulin-dependent protein kinase I. J Neurosci. 2004 Apr 14;24(15):3786-94. PMID:15084659 doi:10.1523/JNEUROSCI.3294-03.2004
- ↑ Schmitt JM, Guire ES, Saneyoshi T, Soderling TR. Calmodulin-dependent kinase kinase/calmodulin kinase I activity gates extracellular-regulated kinase-dependent long-term potentiation. J Neurosci. 2005 Feb 2;25(5):1281-90. PMID:15689566 doi:10.1523/JNEUROSCI.4086-04.2005
- ↑ Tokumitsu H, Hatano N, Yokokura S, Sueyoshi Y, Nozaki N, Kobayashi R. Phosphorylation of Numb regulates its interaction with the clathrin-associated adaptor AP-2. FEBS Lett. 2006 Oct 16;580(24):5797-801. Epub 2006 Sep 27. PMID:17022975 doi:10.1016/j.febslet.2006.09.043
- ↑ Wayman GA, Impey S, Marks D, Saneyoshi T, Grant WF, Derkach V, Soderling TR. Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron. 2006 Jun 15;50(6):897-909. PMID:16772171 doi:10.1016/j.neuron.2006.05.008
- ↑ Davare MA, Saneyoshi T, Soderling TR. Calmodulin-kinases regulate basal and estrogen stimulated medulloblastoma migration via Rac1. J Neurooncol. 2011 Aug;104(1):65-82. doi: 10.1007/s11060-010-0472-6. Epub 2010, Nov 24. PMID:21107644 doi:10.1007/s11060-010-0472-6
- ↑ Gifford JL, Ishida H, Vogel HJ. Fast methionine-based solution structure determination of calcium-calmodulin complexes. J Biomol NMR. 2011 May;50(1):71-81. Epub 2011 Mar 1. PMID:21360154 doi:10.1007/s10858-011-9495-3
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