HIF1A_MOUSE - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: HIF1A_MOUSE
• UniProt AC: Q61221
• Protein Name: Hypoxia-inducible factor 1-alpha
• Gene Name: Hif1a
• Organism: Mus musculus (Mouse).
• Sequence Length: 836
• Subcellular Localization: Cytoplasm . Nucleus . Nucleus speckle . Colocalizes with HIF3A isoform 2 in the nucleus and speckles (PubMed:21546903). Cytoplasmic in normoxia, nuclear translocation in response to hypoxia (By similarity).
• Protein Description: Functions as a master transcriptional regulator of the adaptive response to hypoxia. Under hypoxic conditions, activates the transcription of over 40 genes, including erythropoietin, glucose transporters, glycolytic enzymes, vascular endothelial growth factor, HILPDA, and other genes whose protein products increase oxygen delivery or facilitate metabolic adaptation to hypoxia. Plays an essential role in embryonic vascularization, tumor angiogenesis and pathophysiology of ischemic disease. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters. [PubMed: 26245371 Activation requires recruitment of transcriptional coactivators such as CREBBP and EP300. Activity is enhanced by interaction with both, NCOA1 or NCOA2. Interaction with redox regulatory protein APEX seems to activate CTAD and potentiates activation by NCOA1 and CREBBP. Involved in the axonal distribution and transport of mitochondria in neurons during hypoxia (By similarity]
• Protein Sequence: MEGAGGENEKKKMSSERRKEKSRDAARSRRSKESEVFYELAHQLPLPHNVSSHLDKASVMRLTISYLRVRKLLDAGGLDSEDEMKAQMDCFYLKALDGFVMVLTDDGDMVYISDNVNKYMGLTQFELTGHSVFDFTHPCDHEEMREMLTHRNGPVRKGKELNTQRSFFLRMKCTLTSRGRTMNIKSATWKVLHCTGHIHVYDTNSNQPQCGYKKPPMTCLVLICEPIPHPSNIEIPLDSKTFLSRHSLDMKFSYCDERITELMGYEPEELLGRSIYEYYHALDSDHLTKTHHDMFTKGQVTTGQYRMLAKRGGYVWVETQATVIYNTKNSQPQCIVCVNYVVSGIIQHDLIFSLQQTESVLKPVESSDMKMTQLFTKVESEDTSCLFDKLKKEPDALTLLAPAAGDTIISLDFGSDDTETEDQQLEDVPLYNDVMFPSSNEKLNINLAMSPLPSSETPKPLRSSADPALNQEVALKLESSPESLGLSFTMPQIQDQPASPSDGSTRQSSPERLLQENVNTPNFSQPNSPSEYCFDVDSDMVNVFKLELVEKLFAEDTEAKNPFSTQDTDLDLEMLAPYIPMDDDFQLRSFDQLSPLESNSPSPPSMSTVTGFQQTQLQKPTITATATTTATTDESKTETKDNKEDIKILIASPSSTQVPQETTTAKASAYSGTHSRTASPDRAGKRVIEQTDKAHPRSLNLSATLNQRNTVPEEELNPKTIASQNAQRKRKMEHDGSLFQAAGIGTLLQQPGDCAPTMSLSWKRVKGFISSEQNGTEQKTIILIPSDLACRLLGQSMDESGLPQLTSYDCEVNAPIQGSRNLLQGEELLRALDQVN

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
66	Phosphorylation	VMRLTISYLRVRKLL HHHHHHHHHHHHHHH	8.48	-
80	Phosphorylation	LDAGGLDSEDEMKAQ HHCCCCCCHHHHHHH	52.57	-
247	Phosphorylation	KTFLSRHSLDMKFSY CCCHHHHCCCCCEEE	25.59	-
357	Phosphorylation	LIFSLQQTESVLKPV HHHHHHHCCCCCCCC	19.78	-
366	Phosphorylation	SVLKPVESSDMKMTQ CCCCCCCCCCCCCEE	31.69	-
402	Hydroxylation	DALTLLAPAAGDTII CHHHEEECCCCCEEE	23.70	-
450	Phosphorylation	LNINLAMSPLPSSET EEEEEEECCCCCCCC	20.06	26370283
457	Phosphorylation	SPLPSSETPKPLRSS CCCCCCCCCCCCCCC	38.26	26370283
545	Acetylation	SDMVNVFKLELVEKL CCCEEEHHHHHHHHH	36.45	-
564	Phosphorylation	TEAKNPFSTQDTDLD CCCCCCCCCCCCCCC	26.81	-
568	Phosphorylation	NPFSTQDTDLDLEML CCCCCCCCCCCHHHH	28.75	-
577	Hydroxylation	LDLEMLAPYIPMDDD CCHHHHCCCCCCCCC	24.51	-
589	Phosphorylation	DDDFQLRSFDQLSPL CCCCCCCCHHHCCCC	41.59	-
602	Phosphorylation	PLESNSPSPPSMSTV CCCCCCCCCCCCHHC	49.62	-
652	Phosphorylation	DIKILIASPSSTQVP HEEEEEECCCCCCCC	20.51	27566939
654	Phosphorylation	KILIASPSSTQVPQE EEEEECCCCCCCCCC	43.45	22942356
656	Phosphorylation	LIASPSSTQVPQETT EEECCCCCCCCCCCC	37.61	22942356
668	Phosphorylation	ETTTAKASAYSGTHS CCCCCCHHHCCCCCC	27.34	-
671	Phosphorylation	TAKASAYSGTHSRTA CCCHHHCCCCCCCCC	36.61	26643407
673	Phosphorylation	KASAYSGTHSRTASP CHHHCCCCCCCCCCC	15.67	23375375
675	Phosphorylation	SAYSGTHSRTASPDR HHCCCCCCCCCCCCC	31.03	24719451
677	Phosphorylation	YSGTHSRTASPDRAG CCCCCCCCCCCCCCC	34.21	23375375
679	Phosphorylation	GTHSRTASPDRAGKR CCCCCCCCCCCCCCH	27.07	23375375
719	Acetylation	PEEELNPKTIASQNA CHHHCCHHHHHHHHH	52.03	-
810	S-nitrosylation	PQLTSYDCEVNAPIQ CCCCCCEEEECCCCC	4.83	-
813	Hydroxylation	TSYDCEVNAPIQGSR CCCEEEECCCCCCCC	20.08	-

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
247	S	Phosphorylation	Kinase	CK1	-	Uniprot
564	S	Phosphorylation	Kinase	GSK3-BETA	Q9WV60	Uniprot
568	T	Phosphorylation	Kinase	GSK3-BETA	Q9WV60	Uniprot
589	S	Phosphorylation	Kinase	PLK3	Q60806	Uniprot
602	S	Phosphorylation	Kinase	GSK3-BETA	Q9WV60	Uniprot
668	S	Phosphorylation	Kinase	PLK3	Q60806	Uniprot
-	K	Ubiquitination	E3 ubiquitin ligase	Vhl	P40338	PMID:22199232

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
247	S	Phosphorylation	Phosphorylation at Ser-247 by CSNK1D/CK1 represses kinase activity and impairs ARNT binding (By similarity).	20889502
402	P	Hydroxylation	In normoxia, is hydroxylated on Pro-402 and Pro-577 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1.	-
545	K	Acetylation	Acetylation of Lys-545 by ARD1 increases interaction with VHL and stimulates subsequent proteasomal degradation.	-
545	K	ubiquitylation	Lys-545 appears to be the principal site of ubiquitination.	-
577	P	Hydroxylation	EGLN3/PHD3 has also been shown to hydroxylate Pro-577.	-
577	P	Hydroxylation	In normoxia, is hydroxylated on Pro-402 and Pro-577 in the oxygen-dependent degradation domain (ODD) by EGLN1/PHD2 and EGLN2/PHD1.	-
719	K	Acetylation	Deacetylation of Lys-719 by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation (By similarity).	-
719	K	Hydroxylation	Deacetylation of Lys-719 by SIRT2 increases its interaction with and hydroxylation by EGLN1 thereby inactivating HIF1A activity by inducing its proteasomal degradation (By similarity).	-
810	C	S-nitrosylation	S-nitrosylation of Cys-810 may be responsible for increased recruitment of p300 coactivator necessary for transcriptional activity of HIF-1 complex.	-
813	N	Hydroxylation	Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-813 (By similarity).	-
813	N	Hydroxylation	In normoxia, is hydroxylated on Asn-813 by HIF1AN, thus abrogating interaction with CREBBP and EP300 and preventing transcriptional activation.	-
813	N	ubiquitylation	Clioquinol, the Cu/Zn-chelator, inhibits ubiquitination through preventing hydroxylation at Asn-813 (By similarity).	-

Disease-associated PTM Sites based on SAP

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

Oops, there are no SNP-PTM records of HIF1A_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
VHL_MOUSE	Vhl	physical	20211142
TLX3_MOUSE	Tlx3	physical	20211142
VHL_MOUSE	Vhl	physical	12468553
BMAL1_MOUSE	Arntl	physical	9704006
ATF4_MOUSE	Atf4	physical	23649506
EGLN2_MOUSE	Egln2	physical	23649506
EGLN1_MOUSE	Egln1	physical	23649506
EGLN3_MOUSE	Egln3	physical	23649506
HS71B_MOUSE	Hspa1b	physical	28116619
HS90A_MOUSE	Hsp90aa1	physical	28116619

Drug and Disease Associations

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