Difference between revisions of "CaMKII"

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CaMKII. Calcium/Calmodulin Dependent Protein Kinase II. Ver. 0.3. This calcium calmodulin-dependent protein kinase is composed of four different chains: alpha, beta, gamma, and delta. An enzyme belongs to the serine/threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily.

https://www.genecards.org/cgi-bin/carddisp.pl?gene=CAMK2A

https://www.genecards.org/cgi-bin/carddisp.pl?gene=CAMK2B

https://www.genecards.org/cgi-bin/carddisp.pl?gene=CAMK2G

https://www.genecards.org/cgi-bin/carddisp.pl?gene=CAMK2D

Ca2+–calmodulindependent kinase isoforms in human skeletal muscle. (Rose 2006) [1]

Detection of multifunctional Ca2+–calmodulin-dependent kinase isoforms in human skeletal muscle. Rat brain (RB) and human skeletal muscle (HSkM) extract proteins were immunoblotted using isoform-specific CaM kinase antibodies. For skeletal muscle CaMKII the bands at 55–60 kDa probably correspond to γ/δ isoforms, whereas the 73 kDa band is likely to be the muscle-specific β isoform splice variant termed βM (Bayer et al. 1998; Damiani et al. 2000).

The relative estimates of the amount of CaMKII isoforms in human skeletal muscle based on proteomics data from (Murgia 2017) [2]

Summary remarks

Under construction.

Structure

(Hudmon 2002) [3] CaMKII is derived from a family of four homologous but distinct genes, with over 30 alternatively spliced isoforms described at present. (Soderling 2001) [4]. Unlike many other protein kinases, CaM-KII does not contain a phosphorylatable residue analogous to the activation domains of CaM-KI and CaM-KIV. Thus, CaM-KII is not phosphorylated or activated by CaM-KK2 However, the unique holoenzyme structure of CaM-KII endows it with unusual regulatory properties required for sensing and transducing various types of intracellular Ca2+ signals. Upon activation by Ca2+/CaM binding, the kinase undergoes immediate autophosphorylation on Thr286 (numbering based on the R isoform). (59) This autophosphorylation occurs within the oligomeric complex (i.e., intramolecular) but between adjacent subunits (intersubunit) that have bound Ca2+/CaM. (63,64) This rapid autophosphorylation on Thr286 has two important regulatory consequences: (1) the subsequent dissociation rate for Ca2+/CaM upon removal of Ca2+ is decreased by several orders of magnitude, (65) and (2) even after full dissociation of Ca2+/CaM, the kinase retains partial activity (i.e., Ca2+/CaM-independent or constitutive activity). Presumably, the stacked hexameric ring structure of the CaM-KII holoenzyme restricts intersubunit autophosphorylation to within each ring. Thus, transient elevation of intracellular Ca2+ can give a prolonged response through the constitutive activity of autophosphorylated CaM-KII, and this property appears to be critical for certain physiological functions of CaM-KII.

Linear diagram of a prototypical CaMKII subunit The catalytic domain is autoinhibited by a pseudosubstrate autoregulatory sequence that is disinhibited following Ca2+/CaM binding. The association domain produces the native form of the enzyme, a multimeric holoenzyme composed of 12 subunits. Isoform differences present in the a, b, c and d isoforms of CaMKII are contributed primarily by a region of multiple alternatively spliced sequences, termed variable inserts, which reside in the association domain. Conserved sites of autophosphorylation are indicated in the autoregulatory region. (Soderling 2001) [4]. In the absence of bound Ca2+/CaM, the CaM-KII is maintained in an inactive conformation due to an interaction of an AID with the catalytic domain of its own subunit. Interestingly, the sensitivity of CaMKII to activation by Ca2+/CaM is dictated by the subunit composition of the holoenzyme. (Brocke ‎1999) [5].

The holoenzyme model (Rosenberg 2005) [6]. Iinactive CaMKII forms tightly packed autoinhibited assemblies that convert upon activation into clusters of loosely tethered and independent kinase domains.

CaMKII undergoes multiple autoregulatory states that may have an impact on its function following Ca2+/CaM activation. The multimeric holoenzyme structure of CaMKII is depicted as a 6-mer for simplicity, with activated catalytic subunits illustrated in red. In addition to the Ca2+/CaM-dependent form of the enzyme phosphorylating physiological targets throughout the cell, autophosphorylation produces functional changes in CaMKII (autonomous activity, CaM trapping, CaM capping) that may alter further its activity, regulation, and function.

The autophosphorylation of CaMKII requires coincident Ca2+/CaM binding between neighbouring subunits within the holoenzyme. The catalytic/autoregulatory region is shown for each subunit. In the absence of Ca2+/CaM, the blue autoregulatory domain inhibits catalytic activity (inactivity illustrated in red). Ca2+/CaM binding to each subunit independently disinhibits the autoregulatory region to produce catalytic activity (green). Activated subunits may then act as both kinase and substrate in an intersubunit ± intraholoenzyme autophosphorylation reaction of Thr286 (shown as ` T ' within the red circle). Only the autophosphorylated subunit retains activity in the absence of Ca2+/CaM. Although this autonomous activity is uncoupled from its dependence on Ca2+/CaM, this enzymic state is sensitive to phosphatase activity.

A model encompassing the biophysical and enzymic characteristics of CaMKII displays a non-linear Ca2+ spike frequency-dependence in the generation of autonomous activity (left) and the role of coincident CaM binding, autophosphorylation and CaM trapping in Ca2+-spike frequency detection (right). Inactive subunits within CaMKII holoenzymes (shown as 6-mers for simplicity) are represented by open circles. Ca2+/CaM (blue circle) binding activates a given subunit (shown in red) and coincident Ca2+/CaM binding results in autophosphorylation and CaM trapping ('P' inside a filled dark red circle). During low-frequency Ca2+ spikes, CaM completely dissociates between Ca2+ spikes, effectively producing 'naive' CaMKII subunits at each inner spike interval. However, at high Ca2+ spike frequencies, CaM does not completely dissociate between Ca2+ spikes, which increases the probability that coincident CaM binding, autophosphorylation, and CaM trapping may occur; a process that effectively increases the probability that a neighboring subunit will also bind Ca2+/CaM during successive spikes to produce the dramatic non-linear increase in autonomous activity.

Action

(Sacchetto et al., 2005) http://www.bio.unipd.it/bam/PDF/15-1/04569SacchettoDamiani.pdf

In slow-twitch muscle, CaMKII is mainly involved in regulation of SR Ca2+-transport, as indicated by phosphorylation of SERCA2a isoform of Ca2+-ATPase and of SERCA2a-regulatory protein phospholamban. In fast-twitch muscle, the main role of CaMKII seems to be the control of Ca2+- release. Much experimental evidence seems to negate that ryanodine receptor/SR Ca2+- release channel of skeletal muscle (RyR1) is a substrate of phosphorylation of endogenous CaMKII.

Location

(Sacchetto et al., 2005) http://www.bio.unipd.it/bam/PDF/15-1/04569SacchettoDamiani.pdf

CaMKII is localized on the cytoplasmic side of SR membranes, and is ubiquitously distributed between longitudinal SR and junctional SR.

(Chin 2005) [7], The CaMKII isoform designated CaMKII-βM is predominantly associated with skeletal muscle SR and is anchored there by a truncated, non-kinase protein α-KAP, which is a splice variant of CaMKII- α (4). Furthermore, the various CaMKII- βM splice variants (-β, -βM and - βe’) have similar specific activity but differential sensitivities to Ca2+ due to differences in their CaM activation constant and thus initial rates of autophosphorylation (5).

The majority (i.e. ∼80%) of CaMKII that is expressed in human skeletal muscle is localized to the soluble cytosolic fraction. The majority of work that has been conducted has examined the functional properties and substrates of membrane-associated CaMKII (present study; Sacchetto et al. 2005a). Thus, it is clear that future work should focus on examining the potential substrates and functions of cytosolic CaMKII. (Rose 2006) [1]

Pathways

Upstream

Ca2+/CaM, (Hudmon 2002) [3].

PP1, protein phosphatase-1, (Sacchetto 2005b) [8].

Downstream

PLN, SRF, GS, NR2B, SERCA, CREB, c-fos, FAP, AP-1, GAPDH

Phospholamban (Sacchetto et al., 2005) http://www.bio.unipd.it/bam/PDF/15-1/04569SacchettoDamiani.pdf

Phospholamban (PLN) was the only identified substrate of CaMKII in human skeletal muscle (Margreth et al. 2000) www.bio.unipd.it/bam/PDF/10-4/00442Margreth.pdf, (Rose 2006) [1].

SRF (Flück ‎2000) [9], Isoforms of CaMKII enriched from skeletal muscle phosphorylated SRF in vitro (Fluck 2000b) [10].

GS SR-associated glycogen synthase (GS) was phosphorylated in vitro by SR-bound Ca2+-calmodulin-dependent protein kinase (CaMKII) (Sacchetto 2007) [11].

CaMKII was shown to phosphorylate serum response factor (SRF). Other known substrates of CaMKII include NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor (44), NF-B (24), cardiac calcium release channel (20), SERCA (57), and CREB (45). Other known intermediates for CaMKII signaling include c-fos, FAP, and AP-1 (51). Thus CaMKII may activate transcription directly through posttranslational modification of transcription factors (i.e., SRF, CREB, c-fos, FAP, AP-1). (Chin 2005) [7].

RyR1 is a substrate of phosphorylation of endogenous CaMKII. (Sacchetto et al., 2005) http://www.bio.unipd.it/bam/PDF/15-1/04569SacchettoDamiani.pdf

It has also been shown that skeletal muscle CaMKII can phosphorylate glyceraldehyde-3-phosphate dehydrogenase (Sacchetto et al. 2005b; Singh et al. 2004)… and the glycogen and protein phosphatase-1c targeting subunit GM (Sacchetto et al. 2005b) in a Ca2+–CaM-dependent manner. (Rose 2006) [1].

Kinetics

(Gaertner 2004) [12] 

Interestingly, the rank order of CaM binding affinity (γ > β > δ > α) does not directly correlate with the rank order of their CaM dependence for autophosphorylation (β > γ > δ > α ). Simulations utilizing this data revealed that the measured differences in CaM binding affinities play a minor role in the autophosphorylation of the enzyme, which is largely dictated by the rate of autophosphorylation for each isoform.

Dependence of CaM-kinase II activity on CaM

Dependence of CaM-kinase II autophosphorylation on CaM

References

1. Rose AJ, Kiens B, and Richter EA. Ca2+-calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise. J Physiol. 2006 Aug 1;574(Pt 3):889-903. DOI:10.1113/jphysiol.2006.111757 | PubMed ID:16690701 | HubMed [1]
2. Murgia M, Toniolo L, Nagaraj N, Ciciliot S, Vindigni V, Schiaffino S, Reggiani C, and Mann M. Single Muscle Fiber Proteomics Reveals Fiber-Type-Specific Features of Human Muscle Aging. Cell Rep. 2017 Jun 13;19(11):2396-2409. DOI:10.1016/j.celrep.2017.05.054 | PubMed ID:28614723 | HubMed [2]
3. Hudmon A and Schulman H. Structure-function of the multifunctional Ca2+/calmodulin-dependent protein kinase II. Biochem J. 2002 Jun 15;364(Pt 3):593-611. DOI:10.1042/BJ20020228 | PubMed ID:11931644 | HubMed [3]
4. Soderling TR and Stull JT. Structure and regulation of calcium/calmodulin-dependent protein kinases. Chem Rev. 2001 Aug;101(8):2341-52. DOI:10.1021/cr0002386 | PubMed ID:11749376 | HubMed [4]
5. Brocke L, Chiang LW, Wagner PD, and Schulman H. Functional implications of the subunit composition of neuronal CaM kinase II. J Biol Chem. 1999 Aug 6;274(32):22713-22. DOI:10.1074/jbc.274.32.22713 | PubMed ID:10428854 | HubMed [5]
6. Rosenberg OS, Deindl S, Sung RJ, Nairn AC, and Kuriyan J. Structure of the autoinhibited kinase domain of CaMKII and SAXS analysis of the holoenzyme. Cell. 2005 Dec 2;123(5):849-60. DOI:10.1016/j.cell.2005.10.029 | PubMed ID:16325579 | HubMed [6]
7. Chin ER. Role of Ca2+/calmodulin-dependent kinases in skeletal muscle plasticity. J Appl Physiol (1985). 2005 Aug;99(2):414-23. DOI:10.1152/japplphysiol.00015.2005 | PubMed ID:16020436 | HubMed [7]
8. Sacchetto R, Bovo E, Donella-Deana A, and Damiani E. Glycogen- and PP1c-targeting subunit GM is phosphorylated at Ser48 by sarcoplasmic reticulum-bound Ca2+-calmodulin protein kinase in rabbit fast twitch skeletal muscle. J Biol Chem. 2005 Feb 25;280(8):7147-55. DOI:10.1074/jbc.M413574200 | PubMed ID:15591318 | HubMed [8]
9. Flück M, Waxham MN, Hamilton MT, and Booth FW. Skeletal muscle Ca(2+)-independent kinase activity increases during either hypertrophy or running. J Appl Physiol (1985). 2000 Jan;88(1):352-8. DOI:10.1152/jappl.2000.88.1.352 | PubMed ID:10642401 | HubMed [9]
10. Flück M, Booth FW, and Waxham MN. Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. Biochem Biophys Res Commun. 2000 Apr 13;270(2):488-94. DOI:10.1006/bbrc.2000.2457 | PubMed ID:10753652 | HubMed [10]
11. Sacchetto R, Bovo E, Salviati L, Damiani E, and Margreth A. Glycogen synthase binds to sarcoplasmic reticulum and is phosphorylated by CaMKII in fast-twitch skeletal muscle. Arch Biochem Biophys. 2007 Mar 1;459(1):115-21. DOI:10.1016/j.abb.2006.11.004 | PubMed ID:17178096 | HubMed [11]
12. Gaertner TR, Kolodziej SJ, Wang D, Kobayashi R, Koomen JM, Stoops JK, and Waxham MN. Comparative analyses of the three-dimensional structures and enzymatic properties of alpha, beta, gamma and delta isoforms of Ca2+-calmodulin-dependent protein kinase II. J Biol Chem. 2004 Mar 26;279(13):12484-94. DOI:10.1074/jbc.M313597200 | PubMed ID:14722083 | HubMed [12]