RORA_HUMAN - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: RORA_HUMAN
• UniProt AC: P35398
• Protein Name: Nuclear receptor ROR-alpha
• Gene Name: RORA
• Organism: Homo sapiens (Human).
• Sequence Length: 523
• Subcellular Localization: Nucleus .
• Protein Description: Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium-mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, ARNTL/BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling..
• Protein Sequence: MESAPAAPDPAASEPGSSGADAAAGSRETPLNQESARKSEPPAPVRRQSYSSTSRGISVTKKTHTSQIEIIPCKICGDKSSGIHYGVITCEGCKGFFRRSQQSNATYSCPRQKNCLIDRTSRNRCQHCRLQKCLAVGMSRDAVKFGRMSKKQRDSLYAEVQKHRMQQQQRDHQQQPGEAEPLTPTYNISANGLTELHDDLSNYIDGHTPEGSKADSAVSSFYLDIQPSPDQSGLDINGIKPEPICDYTPASGFFPYCSFTNGETSPTVSMAELEHLAQNISKSHLETCQYLREELQQITWQTFLQEEIENYQNKQREVMWQLCAIKITEAIQYVVEFAKRIDGFMELCQNDQIVLLKAGSLEVVFIRMCRAFDSQNNTVYFDGKYASPDVFKSLGCEDFISFVFEFGKSLCSMHLTEDEIALFSAFVLMSADRSWLQEKVKIEKLQQKIQLALQHVLQKNHREDGILTKLICKVSTLRALCGRHTEKLMAFKAIYPDIVRLHFPPLYKELFTSEFEPAMQIDG

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
35	Phosphorylation	ETPLNQESARKSEPP CCCCCHHHHHHCCCC	14.30	-
38	Methylation	LNQESARKSEPPAPV CCHHHHHHCCCCCCC	22.78	23063525
49	O-linked_Glycosylation	PAPVRRQSYSSTSRG CCCCCCCCCCCCCCC	5.81	30379171
49	Phosphorylation	PAPVRRQSYSSTSRG CCCCCCCCCCCCCCC	5.81	26699800
51	Phosphorylation	PVRRQSYSSTSRGIS CCCCCCCCCCCCCEE	32.11	26699800
79	Acetylation	PCKICGDKSSGIHYG EEEECCCCCCCCEEE	52.46	30595301
102 (in isoform 4)	Phosphorylation	-	23.84	27642862
128 (in isoform 4)	Phosphorylation	-	30.88	-
155	Phosphorylation	MSKKQRDSLYAEVQK CCHHHHHHHHHHHHH	33.72	30206219
157	Phosphorylation	KKQRDSLYAEVQKHR HHHHHHHHHHHHHHH	21.99	28796482
183	Phosphorylation	PGEAEPLTPTYNISA CCCCCCCCCCCEECC	43.51	29656859
216	Phosphorylation	PEGSKADSAVSSFYL CCCCCCCCCHHEEEE	25.05	17512500
240	Sumoylation	GLDINGIKPEPICDY CCCCCCCCCCCCCCC	34.20	19041634
273	Sumoylation	PTVSMAELEHLAQNI CCCCHHHHHHHHHHH	44.73	-
328	O-linked_Glycosylation	QLCAIKITEAIQYVV HHHHHHHHHHHHHHH	3.78	30379171

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
35	S	Phosphorylation	Kinase	PRKCA	P17252	GPS
100	S	Phosphorylation	Kinase	PKCA	P17252	PSP
128	T	Phosphorylation	Kinase	MAPK1	P28482	GPS
183	T	Phosphorylation	Kinase	MAPK1	P28482	Uniprot

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
38	K	Methylation	[Isoform 1]: monomethylated at Lys-38 by EZH2, this creates a degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin ligase complex.	23063525
38	K	ubiquitylation	[Isoform 1]: monomethylated at Lys-38 by EZH2, this creates a degron recognized by a DCX (DDB1-DCAF1/VPRBP-CUL4A-RBX1) E3 ubiquitin ligase complex.	23063525
183	T	Phosphorylation	Phosphorylated on Thr-183 by MAPK1/ERK1 in vitro.	17512500

Disease-associated PTM Sites based on SAP

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

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

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
EP300_HUMAN	EP300	physical	9862959
CEBPB_HUMAN	CEBPB	physical	19324970
PROX1_HUMAN	PROX1	physical	15604093
PNRC1_HUMAN	PNRC1	physical	15604093
NCOA1_HUMAN	NCOA1	physical	15604093
CSN5_HUMAN	COPS5	physical	15604093
PNRC2_HUMAN	PNRC2	physical	15604093
LMO3_HUMAN	LMO3	physical	16713569
NR0B1_HUMAN	NR0B1	physical	16713569
PRS8_HUMAN	PSMC5	physical	16713569
EZH2_HUMAN	EZH2	physical	23063525
DCAF1_HUMAN	VPRBP	physical	23063525
DDB1_HUMAN	DDB1	physical	23063525
PTBP1_HUMAN	PTBP1	physical	23208419
NCOA1_HUMAN	NCOA1	physical	23975195
PRS8_HUMAN	PSMC5	physical	15604093
NDKB_MOUSE	Nme2	physical	8858107

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.

Related Literatures of Post-Translational Modification

Sumoylation

"SUMOylation of RORalpha potentiates transcriptional activationfunction.";
Hwang E.J., Lee J.M., Jeong J., Park J.H., Yang Y., Lim J.S.,Kim J.H., Baek S.H., Kim K.I.;
Biochem. Biophys. Res. Commun. 378:513-517(2009).
Cited for: SUMOYLATION AT LYS-273, AND MUTAGENESIS OF LYS-273 AND LYS-474.
PubMed: 19041634