dbPTM

E2AK2_HUMAN - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	E2AK2_HUMAN
UniProt AC	P19525
Protein Name	Interferon-induced, double-stranded RNA-activated protein kinase
Gene Name	EIF2AK2
Organism	Homo sapiens (Human).
Sequence Length	551
Subcellular Localization	Cytoplasm. Nucleus. Cytoplasm, perinuclear region. Nuclear localization is elevated in acute leukemia, myelodysplastic syndrome (MDS), melanoma, breast, colon, prostate and lung cancer patient samples or cell lines as well as neurocytes from advanced
Protein Description	IFN-induced dsRNA-dependent serine/threonine-protein kinase which plays a key role in the innate immune response to viral infection and is also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation. Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1). Inhibits viral replication via phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (EIF2S1), this phosphorylation impairs the recycling of EIF2S1 between successive rounds of initiation leading to inhibition of translation which eventually results in shutdown of cellular and viral protein synthesis. Also phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11. In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteosomal degradation. Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding proinflammatory cytokines and IFNs. Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6. Can act as both a positive and negative regulator of the insulin signaling pathway (ISP). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes. Can trigger apoptosis via FADD-mediated activation of CASP8. Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin..
Protein Sequence	MAGDLSAGFFMEELNTYRQKQGVVLKYQELPNSGPPHDRRFTFQVIIDGREFPEGEGRSKKEAKNAAAKLAVEILNKEKKAVSPLLLTTTNSSEGLSMGNYIGLINRIAQKKRLTVNYEQCASGVHGPEGFHYKCKMGQKEYSIGTGSTKQEAKQLAAKLAYLQILSEETSVKSDYLSSGSFATTCESQSNSLVTSTLASESSSEGDFSADTSEINSNSDSLNSSSLLMNGLRNNQRKAKRSLAPRFDLPDMKETKYTVDKRFGMDFKEIELIGSGGFGQVFKAKHRIDGKTYVIKRVKYNNEKAEREVKALAKLDHVNIVHYNGCWDGFDYDPETSDDSLESSDYDPENSKNSSRSKTKCLFIQMEFCDKGTLEQWIEKRRGEKLDKVLALELFEQITKGVDYIHSKKLIHRDLKPSNIFLVDTKQVKIGDFGLVTSLKNDGKRTRSKGTLRYMSPEQISSQDYGKEVDLYALGLILAELLHVCDTAFETSKFFTDLRDGIISDIFDKKEKTLLQKLLSKKPEDRPNTSEILRTLTVWKKSPEKNERHTC

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
2	Acetylation	------MAGDLSAGF ------CCCCCCCCC	21.87	22223895
6	Phosphorylation	--MAGDLSAGFFMEE --CCCCCCCCCCHHH	30.96	21406692
16	Phosphorylation	FFMEELNTYRQKQGV CCHHHHHHHHHHCCE	32.48	21406692
17	Phosphorylation	FMEELNTYRQKQGVV CHHHHHHHHHHCCEE	15.24	21406692
20	Ubiquitination	ELNTYRQKQGVVLKY HHHHHHHHCCEEEEE	39.77	-
27	Phosphorylation	KQGVVLKYQELPNSG HCCEEEEEEECCCCC	11.76	21406692
33	Phosphorylation	KYQELPNSGPPHDRR EEEECCCCCCCCCCE	51.22	29496963
42	Phosphorylation	PPHDRRFTFQVIIDG CCCCCEEEEEEEECC	16.02	28450419
61	Methylation	EGEGRSKKEAKNAAA CCCCCCHHHHHHHHH	65.24	-
69	Methylation	EAKNAAAKLAVEILN HHHHHHHHHHHHHHC	32.05	-
69	Ubiquitination	EAKNAAAKLAVEILN HHHHHHHHHHHHHHC	32.05	-
77	Ubiquitination	LAVEILNKEKKAVSP HHHHHHCHHHCCCCC	68.42	-
80	Ubiquitination	EILNKEKKAVSPLLL HHHCHHHCCCCCEEE	55.93	-
83	Phosphorylation	NKEKKAVSPLLLTTT CHHHCCCCCEEEEEC	18.07	25159151
88	Phosphorylation	AVSPLLLTTTNSSEG CCCCEEEEECCCCCC	31.38	28176443
89	Phosphorylation	VSPLLLTTTNSSEGL CCCEEEEECCCCCCC	24.77	28176443
90	Phosphorylation	SPLLLTTTNSSEGLS CCEEEEECCCCCCCC	28.06	28176443
92	Phosphorylation	LLLTTTNSSEGLSMG EEEEECCCCCCCCHH	27.89	28176443
93	Phosphorylation	LLTTTNSSEGLSMGN EEEECCCCCCCCHHH	37.44	28176443
97	Phosphorylation	TNSSEGLSMGNYIGL CCCCCCCCHHHHHHH	35.19	23403867
101	Phosphorylation	EGLSMGNYIGLINRI CCCCHHHHHHHHHHH	7.22	28176443
115	Phosphorylation	IAQKKRLTVNYEQCA HHHHCCCCCCHHHHH	15.67	28348404
134	Acetylation	GPEGFHYKCKMGQKE CCCCEEEEECCCCCE	20.86	26051181
140	Ubiquitination	YKCKMGQKEYSIGTG EEECCCCCEEECCCC	53.54	-
140	Acetylation	YKCKMGQKEYSIGTG EEECCCCCEEECCCC	53.54	26051181
142	Phosphorylation	CKMGQKEYSIGTGST ECCCCCEEECCCCCC	16.78	-
143	Phosphorylation	KMGQKEYSIGTGSTK CCCCCEEECCCCCCH	18.68	24275569
150	Ubiquitination	SIGTGSTKQEAKQLA ECCCCCCHHHHHHHH	48.08	-
159	Ubiquitination	EAKQLAAKLAYLQIL HHHHHHHHHHHHHHH	28.22	-
162	Phosphorylation	QLAAKLAYLQILSEE HHHHHHHHHHHHCCC	15.02	16373505
167	Phosphorylation	LAYLQILSEETSVKS HHHHHHHCCCCCCCC	34.71	28348404
170	Phosphorylation	LQILSEETSVKSDYL HHHHCCCCCCCCCCC	34.47	28348404
171	Phosphorylation	QILSEETSVKSDYLS HHHCCCCCCCCCCCC	30.72	28348404
179	Phosphorylation	VKSDYLSSGSFATTC CCCCCCCCCCCCCEE	35.54	-
181	Phosphorylation	SDYLSSGSFATTCES CCCCCCCCCCCEECC	17.41	-
242	Phosphorylation	NQRKAKRSLAPRFDL CHHHHHHHCCCCCCC	28.33	20363803
253	Ubiquitination	RFDLPDMKETKYTVD CCCCCCCCCCEEECC	70.39	-
255	Phosphorylation	DLPDMKETKYTVDKR CCCCCCCCEEECCHH	24.67	20068231
257	Phosphorylation	PDMKETKYTVDKRFG CCCCCCEEECCHHCC	21.29	20068231
258	Phosphorylation	DMKETKYTVDKRFGM CCCCCEEECCHHCCC	24.63	20068231
268	Ubiquitination	KRFGMDFKEIELIGS HHCCCCCEEEEEEEC	54.22	21906983
292	Phosphorylation	KHRIDGKTYVIKRVK EEEECCEEEEEEEEE	28.66	28857561
293	Phosphorylation	HRIDGKTYVIKRVKY EEECCEEEEEEEEEE	12.03	17290288
299	Ubiquitination	TYVIKRVKYNNEKAE EEEEEEEEECCHHHH	46.42	21906983
304	Ubiquitination	RVKYNNEKAEREVKA EEEECCHHHHHHHHH	58.64	-
304	Acetylation	RVKYNNEKAEREVKA EEEECCHHHHHHHHH	58.64	25953088
323	Phosphorylation	DHVNIVHYNGCWDGF CCEEEEEECCCCCCC	11.45	24144214
332	Phosphorylation	GCWDGFDYDPETSDD CCCCCCCCCCCCCCC	31.01	26657352
336	Phosphorylation	GFDYDPETSDDSLES CCCCCCCCCCCCCCC	42.73	30576142
337	Phosphorylation	FDYDPETSDDSLESS CCCCCCCCCCCCCCC	37.45	30576142
340	Phosphorylation	DPETSDDSLESSDYD CCCCCCCCCCCCCCC	38.74	25849741
343	Phosphorylation	TSDDSLESSDYDPEN CCCCCCCCCCCCCCC	33.53	30576142
344	Phosphorylation	SDDSLESSDYDPENS CCCCCCCCCCCCCCC	30.71	24144214
346	Phosphorylation	DSLESSDYDPENSKN CCCCCCCCCCCCCCC	35.03	27642862
380	Ubiquitination	TLEQWIEKRRGEKLD CHHHHHHHHHCCCHH	37.96	-
385	Ubiquitination	IEKRRGEKLDKVLAL HHHHHCCCHHHHHHH	65.88	-
388	Ubiquitination	RRGEKLDKVLALELF HHCCCHHHHHHHHHH	49.97	-
400	Ubiquitination	ELFEQITKGVDYIHS HHHHHHHCCCCCHHH	59.57	21906983
404	Phosphorylation	QITKGVDYIHSKKLI HHHCCCCCHHHCCEE	9.72	27642862
407	Phosphorylation	KGVDYIHSKKLIHRD CCCCCHHHCCEECCC	23.17	27251275
408	Ubiquitination	GVDYIHSKKLIHRDL CCCCHHHCCEECCCC	37.12	-
416	Acetylation	KLIHRDLKPSNIFLV CEECCCCCCCCEEEE	51.17	26051181
416	Ubiquitination	KLIHRDLKPSNIFLV CEECCCCCCCCEEEE	51.17	-
426	Ubiquitination	NIFLVDTKQVKIGDF CEEEEECCEEEECCC	48.94	21906983
426	Acetylation	NIFLVDTKQVKIGDF CEEEEECCEEEECCC	48.94	26051181
426	2-Hydroxyisobutyrylation	NIFLVDTKQVKIGDF CEEEEECCEEEECCC	48.94	-
429	Ubiquitination	LVDTKQVKIGDFGLV EEECCEEEECCCEEE	38.18	-
437	Phosphorylation	IGDFGLVTSLKNDGK ECCCEEEEEEECCCC	33.13	30108239
438	Phosphorylation	GDFGLVTSLKNDGKR CCCEEEEEEECCCCC	29.84	30108239
440	Ubiquitination	FGLVTSLKNDGKRTR CEEEEEEECCCCCCC	53.40	-
444	Ubiquitination	TSLKNDGKRTRSKGT EEEECCCCCCCCCCE	54.16	-
446	Phosphorylation	LKNDGKRTRSKGTLR EECCCCCCCCCCEEE	42.66	16179259
451	Phosphorylation	KRTRSKGTLRYMSPE CCCCCCCEEEECCHH	16.29	20685959
454	Phosphorylation	RSKGTLRYMSPEQIS CCCCEEEECCHHHHC	12.69	28985074
456	Phosphorylation	KGTLRYMSPEQISSQ CCEEEECCHHHHCCC	19.15	25159151
462	Phosphorylation	MSPEQISSQDYGKEV CCHHHHCCCCCCCHH	28.80	29396449
465	Phosphorylation	EQISSQDYGKEVDLY HHHCCCCCCCHHHHH	23.59	29759185
476	Ubiquitination	VDLYALGLILAELLH HHHHHHHHHHHHHHH	2.78	21890473
504	Phosphorylation	DLRDGIISDIFDKKE HHCCCHHHHHCCHHH	23.80	20873877
509	Ubiquitination	IISDIFDKKEKTLLQ HHHHHCCHHHHHHHH	52.67	-
509	Acetylation	IISDIFDKKEKTLLQ HHHHHCCHHHHHHHH	52.67	26051181
510	Ubiquitination	ISDIFDKKEKTLLQK HHHHCCHHHHHHHHH	67.31	-
512	Ubiquitination	DIFDKKEKTLLQKLL HHCCHHHHHHHHHHH	54.04	-
517	Ubiquitination	KEKTLLQKLLSKKPE HHHHHHHHHHCCCCC	51.90	21890473
517	Acetylation	KEKTLLQKLLSKKPE HHHHHHHHHHCCCCC	51.90	25953088
521	Ubiquitination	LLQKLLSKKPEDRPN HHHHHHCCCCCCCCC	72.77	-
522	Ubiquitination	LQKLLSKKPEDRPNT HHHHHCCCCCCCCCH	50.71	-
529	Phosphorylation	KPEDRPNTSEILRTL CCCCCCCHHHHHHHH	30.35	27251275
530	Phosphorylation	PEDRPNTSEILRTLT CCCCCCHHHHHHHHC	29.31	27251275
534	Methylation	PNTSEILRTLTVWKK CCHHHHHHHHCCCCC	33.09	115487717
535	Phosphorylation	NTSEILRTLTVWKKS CHHHHHHHHCCCCCC	24.28	-
537	Phosphorylation	SEILRTLTVWKKSPE HHHHHHHCCCCCCCC	24.57	23403867
541	Ubiquitination	RTLTVWKKSPEKNER HHHCCCCCCCCCCCC	56.37	-
542	Phosphorylation	TLTVWKKSPEKNERH HHCCCCCCCCCCCCC	34.27	22617229

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
83	S	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
88	T	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
89	T	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
90	T	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
101	Y	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
162	Y	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
242	S	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
255	T	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
258	T	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
293	Y	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
446	T	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
451	T	Phosphorylation	Kinase	EIF2AK2	P19525	GPS
451	T	Phosphorylation	Kinase	RPS6KA3	P51812	GPS
451	T	Phosphorylation	Kinase	MAPK1	P28482	GPS
451	T	Phosphorylation	Kinase	MAPK14	Q16539	GPS

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
446	T	Phosphorylation	11337501
Autophosphorylation of Thr-451 is dependent on Thr-446 and is stimulated by dsRNA binding and dimerization.
451	T	Phosphorylation	11337501
Autophosphorylation of Thr-451 is dependent on Thr-446 and is stimulated by dsRNA binding and dimerization.

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 E2AK2_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
STAT1_HUMAN	STAT1	physical	9135145
PP1A_HUMAN	PPP1CA	physical	12138106
PRKRA_HUMAN	PRKRA	physical	11985496
P53_HUMAN	TP53	physical	10348343
ILF3_HUMAN	ILF3	physical	11438536
ILF3_HUMAN	ILF3	physical	10320367
2A5A_HUMAN	PPP2R5A	physical	10866685
ILF3_HUMAN	ILF3	physical	11438540
ILF2_HUMAN	ILF2	physical	11438540
ILF3_HUMAN	ILF3	physical	10400669
E2AK2_HUMAN	EIF2AK2	physical	7568151
TRBP2_HUMAN	TARBP2	physical	7568151
TRBP2_HUMAN	TARBP2	physical	11438532
STAT1_HUMAN	STAT1	physical	11278865
M3K5_HUMAN	MAP3K5	physical	12473108
PRKRA_HUMAN	PRKRA	physical	9687506
E2AK2_HUMAN	EIF2AK2	physical	10848580
H2A2C_HUMAN	HIST2H2AC	physical	9447982
PGFRB_HUMAN	PDGFRB	physical	11350938
STAT3_HUMAN	STAT3	physical	11350938
IF2A_HUMAN	EIF2S1	physical	19364808
CCNA2_HUMAN	CCNA2	physical	21903422
DHX9_HUMAN	DHX9	physical	21903422
DICER_HUMAN	DICER1	physical	21903422
EDC4_HUMAN	EDC4	physical	21903422
STAU2_HUMAN	STAU2	physical	21903422
TRBP2_HUMAN	TARBP2	physical	21903422
ZN346_HUMAN	ZNF346	physical	21903422
PRKRA_HUMAN	PRKRA	physical	21903422
STAU1_HUMAN	STAU1	physical	21903422
CC124_HUMAN	CCDC124	physical	21903422
CDK3_HUMAN	CDK3	physical	21903422
EBP2_HUMAN	EBNA1BP2	physical	21903422
SYFB_HUMAN	FARSB	physical	21903422
SPB1_HUMAN	FTSJ3	physical	21903422
NOP53_HUMAN	GLTSCR2	physical	21903422
IFRD1_HUMAN	IFRD1	physical	21903422
NOC3L_HUMAN	NOC3L	physical	21903422
PP1G_HUMAN	PPP1CC	physical	21903422
DHX30_HUMAN	DHX30	physical	21903422
IF6_HUMAN	EIF6	physical	21903422
SYFA_HUMAN	FARSA	physical	21903422
GNL3_HUMAN	GNL3	physical	21903422
NOG1_HUMAN	GTPBP4	physical	21903422
H12_HUMAN	HIST1H1C	physical	21903422
HNRPC_HUMAN	HNRNPC	physical	21903422
HNRC1_HUMAN	HNRNPCL1	physical	21903422
KCD17_HUMAN	KCTD17	physical	21903422
LYAR_HUMAN	LYAR	physical	21903422
MOV10_HUMAN	MOV10	physical	21903422
NOP2_HUMAN	NOP2	physical	21903422
PABP4_HUMAN	PABPC4	physical	21903422
PURA_HUMAN	PURA	physical	21903422
LA_HUMAN	SSB	physical	21903422
TOLIP_HUMAN	TOLLIP	physical	21903422
TOP1_HUMAN	TOP1	physical	21903422
XRN2_HUMAN	XRN2	physical	21903422
IKKA_HUMAN	CHUK	physical	10723127
VATF_HUMAN	ATP6V1F	physical	22939629
JAK1_HUMAN	JAK1	physical	17290288
TYK2_HUMAN	TYK2	physical	17290288
IF2A_HUMAN	EIF2S1	physical	17290288
IL7RA_HUMAN	IL7R	physical	23151878
NPM_HUMAN	NPM1	physical	16957780
DHX9_HUMAN	DHX9	physical	19229320
EIF2A_HUMAN	EIF2A	physical	19229320
E2AK2_HUMAN	EIF2AK2	physical	11447118
IF2B3_HUMAN	IGF2BP3	physical	23455922
PRKRA_HUMAN	PRKRA	physical	23455922
DHX30_HUMAN	DHX30	physical	23455922
IF2B2_HUMAN	IGF2BP2	physical	23455922
TRAF5_HUMAN	TRAF5	physical	15121867
TRAF6_HUMAN	TRAF6	physical	15121867
E2AK2_HUMAN	EIF2AK2	physical	18082144
IF2A_HUMAN	EIF2S1	physical	21368187
TRAF2_HUMAN	TRAF2	physical	25715336
TRAF6_HUMAN	TRAF6	physical	25715336
P53_HUMAN	TP53	physical	19631745
NPM_HUMAN	NPM1	physical	12882984
RL6_HUMAN	RPL6	physical	12882984
RLA0_HUMAN	RPLP0	physical	12882984
RS2_HUMAN	RPS2	physical	12882984
RS3A_HUMAN	RPS3A	physical	12882984
LMNA_HUMAN	LMNA	physical	12882984
E2AK2_HUMAN	EIF2AK2	physical	12882984
IF2A_HUMAN	EIF2S1	physical	12882984

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 E2AK2_HUMAN

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"A quantitative atlas of mitotic phosphorylation."; Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,Elledge S.J., Gygi S.P.; Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83 AND SER-456, AND MASSSPECTROMETRY.	18669648 [Abstract]
"Higher-order substrate recognition of eIF2alpha by the RNA-dependentprotein kinase PKR."; Dar A.C., Dever T.E., Sicheri F.; Cell 122:887-900(2005). Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 258-550 IN COMPLEX WITHEIF2ALPHA, AND PHOSPHORYLATION AT THR-446.	16179258 [Abstract]
"Binding of double-stranded RNA to protein kinase PKR is required fordimerization and promotes critical autophosphorylation events in theactivation loop."; Zhang F., Romano P.R., Nagamura-Inoue T., Tian B., Dever T.E.,Mathews M.B., Ozato K., Hinnebusch A.G.; J. Biol. Chem. 276:24946-24958(2001). Cited for: MUTAGENESIS, AND PHOSPHORYLATION AT THR-446 AND THR-451.	11337501 [Abstract]

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