dbPTM

KCC4_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	KCC4_HUMAN
UniProt AC	Q16566
Protein Name	Calcium/calmodulin-dependent protein kinase type IV
Gene Name	CAMK4
Organism	Homo sapiens (Human).
Sequence Length	473
Subcellular Localization	Cytoplasm. Nucleus. Localized in hippocampal neuron nuclei. In spermatids, associated with chromatin and nuclear matrix (By similarity)..
Protein Description	Calcium/calmodulin-dependent protein kinase that operates in the calcium-triggered CaMKK-CaMK4 signaling cascade and regulates, mainly by phosphorylation, the activity of several transcription activators, such as CREB1, MEF2D, JUN and RORA, which play pivotal roles in immune response, inflammation, and memory consolidation. In the thymus, regulates the CD4(+)/CD8(+) double positive thymocytes selection threshold during T-cell ontogeny. In CD4 memory T-cells, is required to link T-cell antigen receptor (TCR) signaling to the production of IL2, IFNG and IL4 (through the regulation of CREB and MEF2). Regulates the differentiation and survival phases of osteoclasts and dendritic cells (DCs). Mediates DCs survival by linking TLR4 and the regulation of temporal expression of BCL2. Phosphorylates the transcription activator CREB1 on 'Ser-133' in hippocampal neuron nuclei and contribute to memory consolidation and long term potentiation (LTP) in the hippocampus. Can activate the MAP kinases MAPK1/ERK2, MAPK8/JNK1 and MAPK14/p38 and stimulate transcription through the phosphorylation of ELK1 and ATF2. Can also phosphorylate in vitro CREBBP, PRM2, MEF2A and STMN1/OP18..
Protein Sequence	MLKVTVPSCSASSCSSVTASAAPGTASLVPDYWIDGSNRDALSDFFEVESELGRGATSIVYRCKQKGTQKPYALKVLKKTVDKKIVRTEIGVLLRLSHPNIIKLKEIFETPTEISLVLELVTGGELFDRIVEKGYYSERDAADAVKQILEAVAYLHENGIVHRDLKPENLLYATPAPDAPLKIADFGLSKIVEHQVLMKTVCGTPGYCAPEILRGCAYGPEVDMWSVGIITYILLCGFEPFYDERGDQFMFRRILNCEYYFISPWWDEVSLNAKDLVRKLIVLDPKKRLTTFQALQHPWVTGKAANFVHMDTAQKKLQEFNARRKLKAAVKAVVASSRLGSASSSHGSIQESHKASRDPSPIQDGNEDMKAIPEGEKIQGDGAQAAVKGAQAELMKVQALEKVKGADINAEEAPKMVPKAVEDGIKVADLELEEGLAEEKLKTVEEAAAPREGQGSSAVGFEVPQQDVILPEY

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
12	Phosphorylation	TVPSCSASSCSSVTA ECCCCCHHHCCCCEE	18.64	22817900
13	Phosphorylation	VPSCSASSCSSVTAS CCCCCHHHCCCCEEC	20.10	22817900
32	Phosphorylation	TASLVPDYWIDGSNR CCCCCCCEEECCCCC	9.74	-
43	Phosphorylation	GSNRDALSDFFEVES CCCCHHHHHHHHHHH	33.81	27732954
50	Phosphorylation	SDFFEVESELGRGAT HHHHHHHHHHCCCCE	43.21	-
57	O-linked_Glycosylation	SELGRGATSIVYRCK HHHCCCCEEHEEECC	23.08	19506079
57	Phosphorylation	SELGRGATSIVYRCK HHHCCCCEEHEEECC	23.08	-
58	O-linked_Glycosylation	ELGRGATSIVYRCKQ HHCCCCEEHEEECCC	14.99	19506079
66	Ubiquitination	IVYRCKQKGTQKPYA HEEECCCCCCCCCCH	49.79	29967540
70	Ubiquitination	CKQKGTQKPYALKVL CCCCCCCCCCHHHHH	39.57	29967540
75	Ubiquitination	TQKPYALKVLKKTVD CCCCCHHHHHHHHCC	37.03	29967540
82	Ubiquitination	KVLKKTVDKKIVRTE HHHHHHCCHHHHHHH	52.33	29967540
89	Ubiquitination	DKKIVRTEIGVLLRL CHHHHHHHHHHHHHC	27.47	24816145
106	Ubiquitination	PNIIKLKEIFETPTE CCEEEHHHHHCCCCH	64.45	29967540
119	Ubiquitination	TEISLVLELVTGGEL CHHHHEEEHHHCCHH	33.44	29967540
133	Ubiquitination	LFDRIVEKGYYSERD HHHHHHHCCCCCHHH	41.12	-
134	Ubiquitination	FDRIVEKGYYSERDA HHHHHHCCCCCHHHH	17.07	29967540
137	O-linked_Glycosylation	IVEKGYYSERDAADA HHHCCCCCHHHHHHH	20.06	19506079
157	Ubiquitination	EAVAYLHENGIVHRD HHHHHHHHCCCCCCC	55.33	29967540
166	Ubiquitination	GIVHRDLKPENLLYA CCCCCCCCHHHCEEC	55.35	30230243
172	Phosphorylation	LKPENLLYATPAPDA CCHHHCEECCCCCCC	16.17	27642862
182	Ubiquitination	PAPDAPLKIADFGLS CCCCCCCEEHHCCHH	34.49	29967540
189	Phosphorylation	KIADFGLSKIVEHQV EEHHCCHHHHHHCHH	22.25	19506079
189	O-linked_Glycosylation	KIADFGLSKIVEHQV EEHHCCHHHHHHCHH	22.25	19506079
190	Acetylation	IADFGLSKIVEHQVL EHHCCHHHHHHCHHH	56.67	19608861
190	Ubiquitination	IADFGLSKIVEHQVL EHHCCHHHHHHCHHH	56.67	19608861
198	Sulfoxidation	IVEHQVLMKTVCGTP HHHCHHHHHHHCCCC	3.43	21406390
199	Ubiquitination	VEHQVLMKTVCGTPG HHCHHHHHHHCCCCC	33.38	-
200	Phosphorylation	EHQVLMKTVCGTPGY HCHHHHHHHCCCCCC	13.68	8621423
204	Phosphorylation	LMKTVCGTPGYCAPE HHHHHCCCCCCCHHH	14.38	24117733
207	Phosphorylation	TVCGTPGYCAPEILR HHCCCCCCCHHHHHC	6.14	29978859
243	Ubiquitination	CGFEPFYDERGDQFM HCCCCCCCCCCCHHH	39.22	29967540
245	Ubiquitination	FEPFYDERGDQFMFR CCCCCCCCCCHHHHH	51.60	29967540
250	Sulfoxidation	DERGDQFMFRRILNC CCCCCHHHHHHHHCC	1.81	21406390
279	Ubiquitination	NAKDLVRKLIVLDPK CHHHHHHHHHHCCHH	34.78	29967540
286	Ubiquitination	KLIVLDPKKRLTTFQ HHHHCCHHHCCCHHH	50.63	24816145
303	Ubiquitination	QHPWVTGKAANFVHM CCCCHHCCHHCCCCC	34.65	29967540
310	Sulfoxidation	KAANFVHMDTAQKKL CHHCCCCCHHHHHHH	4.04	21406390
315	Acetylation	VHMDTAQKKLQEFNA CCCHHHHHHHHHHHH	53.65	25953088
316	Ubiquitination	HMDTAQKKLQEFNAR CCHHHHHHHHHHHHH	43.24	29967540
331	Ubiquitination	RKLKAAVKAVVASSR HHHHHHHHHHHHHCC	30.64	29967540
331	Acetylation	RKLKAAVKAVVASSR HHHHHHHHHHHHHCC	30.64	25953088
336	Phosphorylation	AVKAVVASSRLGSAS HHHHHHHHCCCCCCC	12.37	-
341	Phosphorylation	VASSRLGSASSSHGS HHHCCCCCCCCCCCC	29.57	21712546
343	Phosphorylation	SSRLGSASSSHGSIQ HCCCCCCCCCCCCCC	33.79	28348404
344	Phosphorylation	SRLGSASSSHGSIQE CCCCCCCCCCCCCCH	26.52	28348404
344	O-linked_Glycosylation	SRLGSASSSHGSIQE CCCCCCCCCCCCCCH	26.52	19506079
345	Phosphorylation	RLGSASSSHGSIQES CCCCCCCCCCCCCHH	29.40	19506079
345	O-linked_Glycosylation	RLGSASSSHGSIQES CCCCCCCCCCCCCHH	29.40	19506079
348	Phosphorylation	SASSSHGSIQESHKA CCCCCCCCCCHHHHC	18.70	30576142
352	Phosphorylation	SHGSIQESHKASRDP CCCCCCHHHHCCCCC	17.57	30177828
354	Acetylation	GSIQESHKASRDPSP CCCCHHHHCCCCCCC	58.29	25953088
354	Ubiquitination	GSIQESHKASRDPSP CCCCHHHHCCCCCCC	58.29	19413330
356	O-linked_Glycosylation	IQESHKASRDPSPIQ CCHHHHCCCCCCCCC	41.86	19506079
356	Phosphorylation	IQESHKASRDPSPIQ CCHHHHCCCCCCCCC	41.86	19413330
360	Phosphorylation	HKASRDPSPIQDGNE HHCCCCCCCCCCCCC	38.64	23401153
369	Sulfoxidation	IQDGNEDMKAIPEGE CCCCCCCCCCCCCCC	2.29	21406390
377	Acetylation	KAIPEGEKIQGDGAQ CCCCCCCCCCCCHHH	51.70	25953088
404	Ubiquitination	VQALEKVKGADINAE HHHHHHHHCCCCCHH	60.49	-
440	Ubiquitination	EEGLAEEKLKTVEEA CCCCHHHHHHHHHHH	46.95	29967540
442	Ubiquitination	GLAEEKLKTVEEAAA CCHHHHHHHHHHHHC	62.69	29967540
456	Phosphorylation	APREGQGSSAVGFEV CCCCCCCCCCCCCCC	13.77	26074081
457	Phosphorylation	PREGQGSSAVGFEVP CCCCCCCCCCCCCCC	33.52	26074081
473	Phosphorylation	QDVILPEY------- CCCCCCCC-------	23.16	26074081

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
12	S	Phosphorylation	Kinase	CAMK4	Q16566	GPS
12	S	Phosphorylation	Kinase	CAMKK1	Q8N5S9	PSP
13	S	Phosphorylation	Kinase	CAMK4	Q16566	GPS
13	S	Phosphorylation	Kinase	CAMKK1	Q8N5S9	PSP
200	T	Phosphorylation	Kinase	KCC1A	Q14012	PhosphoELM
200	T	Phosphorylation	Kinase	CAMKK1	Q8N5S9	Uniprot
200	T	Phosphorylation	Kinase	CAMKK2	Q96RR4	Uniprot
200	T	Phosphorylation	Kinase	CAMK1-FAMILY	-	GPS
336	S	Phosphorylation	Kinase	CAMK4	Q16566	GPS

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
12	S	Phosphorylation	8702940
Autophosphorylated on Ser-12 and Ser-13.
13	S	Phosphorylation	8702940
Autophosphorylated on Ser-12 and Ser-13.
189	S	Glycosylation	19506079
Glycosylation at Ser-189 modulates the phosphorylation of CaMK4 at Thr-200 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation.
189	S	Phosphorylation	19506079
Glycosylation at Ser-189 modulates the phosphorylation of CaMK4 at Thr-200 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation.
200	T	Glycosylation	8702940
Glycosylation at Ser-189 modulates the phosphorylation of CaMK4 at Thr-200 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation.
200	T	Phosphorylation	8702940
Glycosylation at Ser-189 modulates the phosphorylation of CaMK4 at Thr-200 and negatively regulates its activity toward CREB1 in basal conditions and during early inomycin stimulation.
200	T	Phosphorylation	8702940
Phosphorylated by CaMKK1 and CaMKK2 on Thr-200.

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 KCC4_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
HDAC4_HUMAN	HDAC4	physical	11470791
CABIN_HUMAN	CABIN1	physical	15902271
NOTC1_HUMAN	NOTCH1	physical	23103515
GIT1_HUMAN	GIT1	physical	28514442
ARHG7_HUMAN	ARHGEF7	physical	28514442
GIT2_HUMAN	GIT2	physical	28514442
ANR28_HUMAN	ANKRD28	physical	28514442
PP6R2_HUMAN	PPP6R2	physical	28514442
ANR52_HUMAN	ANKRD52	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 KCC4_HUMAN

Related Literatures of Post-Translational Modification

Acetylation
Reference	PubMed
"Lysine acetylation targets protein complexes and co-regulates majorcellular functions."; Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.,Olsen J.V., Mann M.; Science 325:834-840(2009). Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-190, AND MASS SPECTROMETRY.	19608861 [Abstract]
O-linked Glycosylation
Reference	PubMed
"Regulation of calcium/calmodulin-dependent kinase IV by O-GlcNAcmodification."; Dias W.B., Cheung W.D., Wang Z., Hart G.W.; J. Biol. Chem. 284:21327-21337(2009). Cited for: GLYCOSYLATION AT THR-57 SER-58; SER-137; SER-189; SER-344; SER-345 ANDSER-356, PHOSPHORYLATION AT THR-200, IDENTIFICATION BY MASSSPECTROMETRY, AND MUTAGENESIS OF 57-THR-SER-58 AND SER-189.	19506079 [Abstract]
Phosphorylation
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: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-356 AND SER-360, ANDMASS SPECTROMETRY.	19413330 [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-341 AND SER-360, ANDMASS SPECTROMETRY.	17192257 [Abstract]
"A unique phosphorylation-dependent mechanism for the activation ofCa2+/calmodulin-dependent protein kinase type IV/GR."; Chatila T., Anderson K.A., Ho N., Means A.R.; J. Biol. Chem. 271:21542-21548(1996). Cited for: ENZYME REGULATION, PHOSPHORYLATION AT SER-12; SER-13 AND THR-200, ANDMUTAGENESIS OF SER-12 AND SER-13.	8702940 [Abstract]
"Regulation of calcium/calmodulin-dependent kinase IV by O-GlcNAcmodification."; Dias W.B., Cheung W.D., Wang Z., Hart G.W.; J. Biol. Chem. 284:21327-21337(2009). Cited for: GLYCOSYLATION AT THR-57 SER-58; SER-137; SER-189; SER-344; SER-345 ANDSER-356, PHOSPHORYLATION AT THR-200, IDENTIFICATION BY MASSSPECTROMETRY, AND MUTAGENESIS OF 57-THR-SER-58 AND SER-189.	19506079 [Abstract]
"Regulation and function of the calcium/calmodulin-dependent proteinkinase IV/protein serine/threonine phosphatase 2A signaling complex."; Anderson K.A., Noeldner P.K., Reece K., Wadzinski B.E., Means A.R.; J. Biol. Chem. 279:31708-31716(2004). Cited for: ENZYME REGULATION, INTERACTION WITH PROTEIN PHOSPHATASE 2A,PHOSPHORYLATION AT THR-200, AND MUTAGENESIS OF 320-PHE-ASN-321.	15143065 [Abstract]

show

show

show

show

show

show

show