dbPTM

KCC2D_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	KCC2D_HUMAN
UniProt AC	Q13557
Protein Name	Calcium/calmodulin-dependent protein kinase type II subunit delta
Gene Name	CAMK2D
Organism	Homo sapiens (Human).
Sequence Length	499
Subcellular Localization	Cell membrane, sarcolemma Peripheral membrane protein Cytoplasmic side . Sarcoplasmic reticulum membrane Peripheral membrane protein Cytoplasmic side .
Protein Description	Calcium/calmodulin-dependent protein kinase involved in the regulation of Ca(2+) homeostatis and excitation-contraction coupling (ECC) in heart by targeting ion channels, transporters and accessory proteins involved in Ca(2+) influx into the myocyte, Ca(2+) release from the sarcoplasmic reticulum (SR), SR Ca(2+) uptake and Na(+) and K(+) channel transport. Targets also transcription factors and signaling molecules to regulate heart function. In its activated form, is involved in the pathogenesis of dilated cardiomyopathy and heart failure. Contributes to cardiac decompensation and heart failure by regulating SR Ca(2+) release via direct phosphorylation of RYR2 Ca(2+) channel on 'Ser-2808'. In the nucleus, phosphorylates the MEF2 repressor HDAC4, promoting its nuclear export and binding to 14-3-3 protein, and expression of MEF2 and genes involved in the hypertrophic program. Is essential for left ventricular remodeling responses to myocardial infarction. In pathological myocardial remodeling acts downstream of the beta adrenergic receptor signaling cascade to regulate key proteins involved in ECC. Regulates Ca(2+) influx to myocytes by binding and phosphorylating the L-type Ca(2+) channel subunit beta-2 CACNB2. In addition to Ca(2+) channels, can target and regulate the cardiac sarcolemmal Na(+) channel Nav1.5/SCN5A and the K+ channel Kv4.3/KCND3, which contribute to arrhythmogenesis in heart failure. Phosphorylates phospholamban (PLN/PLB), an endogenous inhibitor of SERCA2A/ATP2A2, contributing to the enhancement of SR Ca(2+) uptake that may be important in frequency-dependent acceleration of relaxation (FDAR) and maintenance of contractile function during acidosis. May participate in the modulation of skeletal muscle function in response to exercise, by regulating SR Ca(2+) transport through phosphorylation of PLN/PLB and triadin, a ryanodine receptor-coupling factor..
Protein Sequence	MASTTTCTRFTDEYQLFEELGKGAFSVVRRCMKIPTGQEYAAKIINTKKLSARDHQKLEREARICRLLKHPNIVRLHDSISEEGFHYLVFDLVTGGELFEDIVAREYYSEADASHCIQQILESVNHCHLNGIVHRDLKPENLLLASKSKGAAVKLADFGLAIEVQGDQQAWFGFAGTPGYLSPEVLRKDPYGKPVDMWACGVILYILLVGYPPFWDEDQHRLYQQIKAGAYDFPSPEWDTVTPEAKDLINKMLTINPAKRITASEALKHPWICQRSTVASMMHRQETVDCLKKFNARRKLKGAILTTMLATRNFSAAKSLLKKPDGVKESTESSNTTIEDEDVKARKQEIIKVTEQLIEAINNGDFEAYTKICDPGLTAFEPEALGNLVEGMDFHRFYFENALSKSNKPIHTIILNPHVHLVGDDAACIAYIRLTQYMDGSGMPKTMQSEETRVWHRRDGKWQNVHFHRSGSPTVPIKPPCIPNGKENFSGGTSLWQNI

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
2	Acetylation	------MASTTTCTR ------CCCCCCCCC	18.65	19369195
3	Phosphorylation	-----MASTTTCTRF -----CCCCCCCCCC	25.62	17192257
4	Phosphorylation	----MASTTTCTRFT ----CCCCCCCCCCC	19.31	20068231
5	Phosphorylation	---MASTTTCTRFTD ---CCCCCCCCCCCC	19.85	30576142
6	Phosphorylation	--MASTTTCTRFTDE --CCCCCCCCCCCCH	16.39	21406692
8	Phosphorylation	MASTTTCTRFTDEYQ CCCCCCCCCCCCHHH	27.07	30576142
11	Phosphorylation	TTTCTRFTDEYQLFE CCCCCCCCCHHHHHH	25.32	21406692
14	Phosphorylation	CTRFTDEYQLFEELG CCCCCCHHHHHHHHC	17.21	21406692
26	Phosphorylation	ELGKGAFSVVRRCMK HHCCCHHHHHHHHCC	21.11	28857561
36	Phosphorylation	RRCMKIPTGQEYAAK HHHCCCCCCHHHHHH	55.78	28152594
40	Phosphorylation	KIPTGQEYAAKIINT CCCCCHHHHHHHHHH	12.17	28152594
43	Ubiquitination	TGQEYAAKIINTKKL CCHHHHHHHHHHHCC	35.63	-
57	Ubiquitination	LSARDHQKLEREARI CCHHHHHHHHHHHHH	49.23	-
69	Ubiquitination	ARICRLLKHPNIVRL HHHHHHHCCCCEEEE	62.70	-
79	Phosphorylation	NIVRLHDSISEEGFH CEEEECCCCCCCCCE	19.78	24275569
138	Ubiquitination	GIVHRDLKPENLLLA CCCCCCCCHHHEEEE	55.35	-
146	Phosphorylation	PENLLLASKSKGAAV HHHEEEEECCCCCCE	37.11	28857561
148	Phosphorylation	NLLLASKSKGAAVKL HEEEEECCCCCCEEH	33.55	28122231
182	Phosphorylation	AGTPGYLSPEVLRKD CCCCCCCCHHHHHCC	15.55	21815630
227	Acetylation	HRLYQQIKAGAYDFP HHHHHHHHHCCCCCC	36.11	132789
227	Ubiquitination	HRLYQQIKAGAYDFP HHHHHHHHHCCCCCC	36.11	21906983
227 (in isoform 1)	Ubiquitination	-	36.11	21890473
227 (in isoform 10)	Ubiquitination	-	36.11	21890473
227 (in isoform 11)	Ubiquitination	-	36.11	21890473
227 (in isoform 3)	Ubiquitination	-	36.11	21890473
227 (in isoform 4)	Ubiquitination	-	36.11	21890473
227 (in isoform 5)	Ubiquitination	-	36.11	21890473
227 (in isoform 6)	Ubiquitination	-	36.11	21890473
227 (in isoform 8)	Ubiquitination	-	36.11	21890473
227 (in isoform 9)	Ubiquitination	-	36.11	21890473
231	Phosphorylation	QQIKAGAYDFPSPEW HHHHHCCCCCCCCCC	19.73	28857561
235	Phosphorylation	AGAYDFPSPEWDTVT HCCCCCCCCCCCCCC	35.13	28857561
240	Phosphorylation	FPSPEWDTVTPEAKD CCCCCCCCCCHHHHH	27.61	28857561
246	Ubiquitination	DTVTPEAKDLINKML CCCCHHHHHHHHHHH	51.94	-
251	Ubiquitination	EAKDLINKMLTINPA HHHHHHHHHHCCCHH	28.44	21890473
251	Ubiquitination	EAKDLINKMLTINPA HHHHHHHHHHCCCHH	28.44	2189047
251 (in isoform 1)	Ubiquitination	-	28.44	21890473
251 (in isoform 10)	Ubiquitination	-	28.44	21890473
251 (in isoform 11)	Ubiquitination	-	28.44	21890473
251 (in isoform 3)	Ubiquitination	-	28.44	21890473
251 (in isoform 4)	Ubiquitination	-	28.44	21890473
251 (in isoform 5)	Ubiquitination	-	28.44	21890473
251 (in isoform 6)	Ubiquitination	-	28.44	21890473
251 (in isoform 8)	Ubiquitination	-	28.44	21890473
251 (in isoform 9)	Ubiquitination	-	28.44	21890473
254	Phosphorylation	DLINKMLTINPAKRI HHHHHHHCCCHHHCC	18.40	29396449
259	2-Hydroxyisobutyrylation	MLTINPAKRITASEA HHCCCHHHCCCHHHH	45.66	-
262	Phosphorylation	INPAKRITASEALKH CCHHHCCCHHHHHCC	28.32	23312004
264	Phosphorylation	PAKRITASEALKHPW HHHCCCHHHHHCCCC	18.11	28857561
276	Phosphorylation	HPWICQRSTVASMMH CCCHHCHHHHHHHHH	11.01	23882029
277	Phosphorylation	PWICQRSTVASMMHR CCHHCHHHHHHHHHH	23.45	23663014
280	Phosphorylation	CQRSTVASMMHRQET HCHHHHHHHHHHHHH	16.59	23882029
281	Sulfoxidation	QRSTVASMMHRQETV CHHHHHHHHHHHHHH	1.57	30846556
282	Sulfoxidation	RSTVASMMHRQETVD HHHHHHHHHHHHHHH	1.87	30846556
287	Phosphorylation	SMMHRQETVDCLKKF HHHHHHHHHHHHHHH	17.20	29255136
299	Methylation	KKFNARRKLKGAILT HHHHHHHHHHHHHHH	49.34	-
301	Methylation	FNARRKLKGAILTTM HHHHHHHHHHHHHHH	49.70	-
306	Phosphorylation	KLKGAILTTMLATRN HHHHHHHHHHHHHCC	12.21	21082442
307	Phosphorylation	LKGAILTTMLATRNF HHHHHHHHHHHHCCH	13.52	21082442
308	Sulfoxidation	KGAILTTMLATRNFS HHHHHHHHHHHCCHH	1.70	30846556
311	Phosphorylation	ILTTMLATRNFSAAK HHHHHHHHCCHHHHH	23.37	29514088
315	Phosphorylation	MLATRNFSAAKSLLK HHHHCCHHHHHHHHC	30.76	26055452
318	Acetylation	TRNFSAAKSLLKKPD HCCHHHHHHHHCCCC	41.16	25953088
318	Ubiquitination	TRNFSAAKSLLKKPD HCCHHHHHHHHCCCC	41.16	-
319	Phosphorylation	RNFSAAKSLLKKPDG CCHHHHHHHHCCCCC	33.92	23927012
330	Phosphorylation	KPDGVKESTESSNTT CCCCCCCCCCCCCCC	31.58	29255136
331	Phosphorylation	PDGVKESTESSNTTI CCCCCCCCCCCCCCC	40.76	29255136
332 (in isoform 10)	Phosphorylation	-	62.54	26437602
332 (in isoform 11)	Phosphorylation	-	62.54	-
332 (in isoform 3)	Phosphorylation	-	62.54	27174698
332 (in isoform 6)	Phosphorylation	-	62.54	26437602
332 (in isoform 9)	Phosphorylation	-	62.54	27174698
333	Phosphorylation	GVKESTESSNTTIED CCCCCCCCCCCCCCH	29.04	29255136
333 (in isoform 10)	Phosphorylation	-	29.04	26437602
333 (in isoform 3)	Phosphorylation	-	29.04	27174698
333 (in isoform 6)	Phosphorylation	-	29.04	26437602
333 (in isoform 9)	Phosphorylation	-	29.04	27174698
334	Phosphorylation	VKESTESSNTTIEDE CCCCCCCCCCCCCHH	31.78	22167270
334 (in isoform 3)	Phosphorylation	-	31.78	27174698
334 (in isoform 9)	Phosphorylation	-	31.78	27174698
335 (in isoform 3)	Phosphorylation	-	50.99	27174698
335 (in isoform 9)	Phosphorylation	-	50.99	27174698
336	Phosphorylation	ESTESSNTTIEDEDV CCCCCCCCCCCHHHH	30.97	29255136
337	Phosphorylation	STESSNTTIEDEDVK CCCCCCCCCCHHHHH	26.98	29255136
337 (in isoform 4)	Phosphorylation	-	26.98	26270265
337 (in isoform 5)	Phosphorylation	-	26.98	26270265
338 (in isoform 4)	Phosphorylation	-	6.21	26270265
338 (in isoform 5)	Phosphorylation	-	6.21	26270265
341 (in isoform 3)	Phosphorylation	-	52.49	27174698
341 (in isoform 9)	Phosphorylation	-	52.49	27174698
342 (in isoform 3)	Phosphorylation	-	60.58	27174698
342 (in isoform 9)	Phosphorylation	-	60.58	27174698
344 (in isoform 11)	Phosphorylation	-	55.59	26437602
344 (in isoform 3)	Phosphorylation	-	55.59	27174698
344 (in isoform 9)	Phosphorylation	-	55.59	27174698
345 (in isoform 10)	Phosphorylation	-	24.61	26657352
345 (in isoform 3)	Phosphorylation	-	24.61	27174698
345 (in isoform 6)	Phosphorylation	-	24.61	26657352
345 (in isoform 9)	Phosphorylation	-	24.61	27174698
347 (in isoform 3)	Phosphorylation	-	58.08	27174698
347 (in isoform 9)	Phosphorylation	-	58.08	27174698
348 (in isoform 3)	Phosphorylation	-	41.38	27174698
348 (in isoform 9)	Phosphorylation	-	41.38	27174698
350 (in isoform 10)	Phosphorylation	-	3.24	26657352
350 (in isoform 6)	Phosphorylation	-	3.24	26657352
356 (in isoform 11)	Phosphorylation	-	38.07	26657352
361 (in isoform 11)	Phosphorylation	-	2.39	26657352
373	S-nitrosocysteine	FEAYTKICDPGLTAF HHHHHHCCCCCCCCC	5.71	-
373	S-nitrosylation	FEAYTKICDPGLTAF HHHHHHCCCCCCCCC	5.71	21278135
398	Phosphorylation	GMDFHRFYFENALSK CCCHHHHHHHHHHCC	15.22	28152594
404	Phosphorylation	FYFENALSKSNKPIH HHHHHHHCCCCCCCE	31.46	22817900
441	Phosphorylation	LTQYMDGSGMPKTMQ HHHHCCCCCCCCCCC	27.88	22817900
470	Phosphorylation	QNVHFHRSGSPTVPI EEEEEECCCCCCCCC	34.74	30108239
470 (in isoform 12)	Phosphorylation	-	34.74	30108239
472	Phosphorylation	VHFHRSGSPTVPIKP EEEECCCCCCCCCCC	20.74	23927012
472 (in isoform 12)	Phosphorylation	-	20.74	29514088
472 (in isoform 8)	Phosphorylation	-	20.74	18691976
474	Phosphorylation	FHRSGSPTVPIKPPC EECCCCCCCCCCCCC	40.38	28450419
474 (in isoform 12)	Phosphorylation	-	40.38	29514088
483 (in isoform 9)	Phosphorylation	-	50.68	18691976
486 (in isoform 10)	Phosphorylation	-	57.00	18691976
490	Phosphorylation	PNGKENFSGGTSLWQ CCCCCCCCCCCCCCC	48.14	29514088
492 (in isoform 5)	Phosphorylation	-	15.78	18691976
493	Phosphorylation	KENFSGGTSLWQNI- CCCCCCCCCCCCCC-	24.95	24719451
494	Phosphorylation	ENFSGGTSLWQNI-- CCCCCCCCCCCCC--	30.77	29514088

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
287	T	Phosphorylation	Kinase	CAMK2D	Q13557	GPS
307	T	Phosphorylation	Kinase	CAMK2D	Q13557	GPS

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
287	T	Phosphorylation	16690701
Autophosphorylation of Thr-287 following activation by Ca(2+)/calmodulin.
287	T	Phosphorylation	16690701
Phosphorylation of Thr-287 locks the kinase into an activated state.

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Modified Location	Modification	Variant Position (Distance <= 10)	Residue Change	SAP	Related Disease	Reference
Oops, there are no SNP-PTM records of KCC2D_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
RS18_HUMAN	RPS18	physical	12145273
HDAC4_HUMAN	HDAC4	physical	17179159
HDAC4_HUMAN	HDAC4	physical	16767219
WASF3_HUMAN	WASF3	physical	21988832
F171B_HUMAN	FAM171B	physical	21988832
HNMT_HUMAN	HNMT	physical	21988832
INGR2_HUMAN	IFNGR2	physical	21988832
RS4X_HUMAN	RPS4X	physical	21988832
SPA24_HUMAN	SPATA24	physical	21988832
KCC2D_HUMAN	CAMK2D	physical	25416956
FKB1B_HUMAN	FKBP1B	physical	25416956
FXR2_HUMAN	FXR2	physical	25416956
DNAL4_HUMAN	DNAL4	physical	25416956
TNPO2_HUMAN	TNPO2	physical	25416956
BANP_HUMAN	BANP	physical	25416956
MOAP1_HUMAN	MOAP1	physical	25416956
FND3B_HUMAN	FNDC3B	physical	25416956
RM11_HUMAN	MRPL11	physical	25416956
TTC5_HUMAN	TTC5	physical	25416956
EPHAA_HUMAN	EPHA10	physical	25416956
KCC2D_HUMAN	CAMK2D	physical	18082144
KCC2A_HUMAN	CAMK2A	physical	28514442
KCC2B_HUMAN	CAMK2B	physical	28514442
KCC2G_HUMAN	CAMK2G	physical	28514442
DYH14_HUMAN	DNAH14	physical	28514442
UNG_HUMAN	UNG	physical	28514442
BAP1_HUMAN	BAP1	physical	28514442
KANL3_HUMAN	KANSL3	physical	28514442
MRM2_HUMAN	FTSJ2	physical	28514442
PUSL1_HUMAN	PUSL1	physical	28514442
MTG1_HUMAN	MTG1	physical	28514442
MOK_HUMAN	MOK	physical	28514442
CXXC1_HUMAN	CXXC1	physical	28514442
ZBTB2_HUMAN	ZBTB2	physical	28514442
WDR76_HUMAN	WDR76	physical	28514442
DIDO1_HUMAN	DIDO1	physical	28514442
SET1A_HUMAN	SETD1A	physical	28514442
SENP5_HUMAN	SENP5	physical	28514442
ELP3_HUMAN	ELP3	physical	28514442
NEDD1_HUMAN	NEDD1	physical	28514442
SUH_HUMAN	RBPJ	physical	28514442
LIN54_HUMAN	LIN54	physical	28514442
TRM61_HUMAN	TRMT61A	physical	28514442
PI51A_HUMAN	PIP5K1A	physical	28514442
MAP7_HUMAN	MAP7	physical	28514442
ZRAB3_HUMAN	ZRANB3	physical	28514442
BD1L1_HUMAN	BOD1L1	physical	28514442
CU002_HUMAN	C21orf2	physical	28514442
DTL_HUMAN	DTL	physical	28514442
HEM1_HUMAN	ALAS1	physical	28514442
TPRN_HUMAN	TPRN	physical	28514442
HCFC1_HUMAN	HCFC1	physical	28514442
NEK1_HUMAN	NEK1	physical	28514442
DPH1_HUMAN	DPH1	physical	28514442
OGT1_HUMAN	OGT	physical	28514442
TSR3_HUMAN	TSR3	physical	28514442
THUM3_HUMAN	THUMPD3	physical	28514442

Drug and Disease Associations

Kegg Disease
There are no disease associations of PTM sites.
OMIM Disease
There are no disease associations of PTM sites.
Kegg Drug
There are no disease associations of PTM sites.
DrugBank
There are no disease associations of PTM sites.

Regulatory Network of KCC2D_HUMAN

Related Literatures of Post-Translational Modification

Acetylation
Reference	PubMed
"Lys-N and trypsin cover complementary parts of the phosphoproteome ina refined SCX-based approach."; Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,Mohammed S.; Anal. Chem. 81:4493-4501(2009). Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGESCALE ANALYSIS] AT SER-333, AND MASS SPECTROMETRY.	19413330 [Abstract]
Phosphorylation
Reference	PubMed
"Large-scale proteomics analysis of the human kinome."; Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,Mann M., Daub H.; Mol. Cell. Proteomics 8:1751-1764(2009). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; THR-287; THR-306;THR-307; SER-315; SER-319; SER-330; THR-331; SER-333; SER-334;THR-336; THR-337; SER-404; SER-441; SER-470; SER-472 AND SER-490, ANDMASS SPECTROMETRY.	19369195 [Abstract]
"Lys-N and trypsin cover complementary parts of the phosphoproteome ina refined SCX-based approach."; Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,Mohammed S.; Anal. Chem. 81:4493-4501(2009). Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGESCALE ANALYSIS] AT SER-333, AND MASS SPECTROMETRY.	19413330 [Abstract]
"Large-scale phosphoproteome analysis of human liver tissue byenrichment and fractionation of phosphopeptides with strong anionexchange chromatography."; Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D.,Zou H., Gu J.; Proteomics 8:1346-1361(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-330; THR-331; SER-333AND THR-337, AND MASS SPECTROMETRY.	18318008 [Abstract]
"Kinase-selective enrichment enables quantitative phosphoproteomics ofthe kinome across the cell cycle."; Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,Greff Z., Keri G., Stemmann O., Mann M.; Mol. Cell 31:438-448(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; SER-315; SER-319;THR-331 AND SER-472, AND MASS SPECTROMETRY.	18691976 [Abstract]
"Proteomics analysis of protein kinases by target class-selectiveprefractionation and tandem mass spectrometry."; Wissing J., Jaensch L., Nimtz M., Dieterich G., Hornberger R.,Keri G., Wehland J., Daub H.; Mol. Cell. Proteomics 6:537-547(2007). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-315; SER-319 ANDTHR-337, AND MASS SPECTROMETRY.	17192257 [Abstract]
"Ca2+-calmodulin-dependent protein kinase expression and signalling inskeletal muscle during exercise."; Rose A.J., Kiens B., Richter E.A.; J. Physiol. (Lond.) 574:889-903(2006). Cited for: FUNCTION IN SKELETAL MUSCLE, PHOSPHORYLATION AT THR-287, FUNCTION INPHOSPHORYLATION OF PLN, TISSUE SPECIFICITY, AND INDUCTION.	16690701 [Abstract]
"Global, in vivo, and site-specific phosphorylation dynamics insignaling networks."; Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,Mann M.; Cell 127:635-648(2006). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-337, AND MASSSPECTROMETRY.	17081983 [Abstract]

show

show