NR1D1_HUMAN - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: NR1D1_HUMAN
• UniProt AC: P20393
• Protein Name: Nuclear receptor subfamily 1 group D member 1
• Gene Name: NR1D1
• Organism: Homo sapiens (Human).
• Sequence Length: 614
• Subcellular Localization: Nucleus. Cytoplasm. Cell projection, dendrite. Cell projection, dendritic spine. Localizes to the cytoplasm, dendrites and dendritic spine in the presence of OPHN1..
• Protein Description: Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner..
• Protein Sequence: MTTLDSNNNTGGVITYIGSSGSSPSRTSPESLYSDNSNGSFQSLTQGCPTYFPPSPTGSLTQDPARSFGSIPPSLSDDGSPSSSSSSSSSSSSFYNGSPPGSLQVAMEDSSRVSPSKSTSNITKLNGMVLLCKVCGDVASGFHYGVHACEGCKGFFRRSIQQNIQYKRCLKNENCSIVRINRNRCQQCRFKKCLSVGMSRDAVRFGRIPKREKQRMLAEMQSAMNLANNQLSSQCPLETSPTQHPTPGPMGPSPPPAPVPSPLVGFSQFPQQLTPPRSPSPEPTVEDVISQVARAHREIFTYAHDKLGSSPGNFNANHASGSPPATTPHRWENQGCPPAPNDNNTLAAQRHNEALNGLRQAPSSYPPTWPPGPAHHSCHQSNSNGHRLCPTHVYAAPEGKAPANSPRQGNSKNVLLACPMNMYPHGRSGRTVQEIWEDFSMSFTPAVREVVEFAKHIPGFRDLSQHDQVTLLKAGTFEVLMVRFASLFNVKDQTVMFLSRTTYSLQELGAMGMGDLLSAMFDFSEKLNSLALTEEELGLFTAVVLVSADRSGMENSASVEQLQETLLRALRALVLKNRPLETSRFTKLLLKLPDLRTLNNMHSEKLLSFRVDAQ

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
2	Phosphorylation	------MTTLDSNNN ------CCEECCCCC	35.75	22210691
3	Phosphorylation	-----MTTLDSNNNT -----CCEECCCCCC	27.54	22210691
6	Phosphorylation	--MTTLDSNNNTGGV --CCEECCCCCCCCE	44.57	22210691
10	Phosphorylation	TLDSNNNTGGVITYI EECCCCCCCCEEEEE	37.12	22210691
19	Phosphorylation	GVITYIGSSGSSPSR CEEEEECCCCCCCCC	23.20	26074081
20	Phosphorylation	VITYIGSSGSSPSRT EEEEECCCCCCCCCC	37.16	26074081
22	Phosphorylation	TYIGSSGSSPSRTSP EEECCCCCCCCCCCH	40.81	25159151
23	Phosphorylation	YIGSSGSSPSRTSPE EECCCCCCCCCCCHH	30.35	25159151
25	Phosphorylation	GSSGSSPSRTSPESL CCCCCCCCCCCHHHH	50.57	26074081
27	Phosphorylation	SGSSPSRTSPESLYS CCCCCCCCCHHHHCC	53.63	26074081
55	Phosphorylation	CPTYFPPSPTGSLTQ CCCCCCCCCCCCCCC	35.02	22817900
59	Phosphorylation	FPPSPTGSLTQDPAR CCCCCCCCCCCCHHH	30.62	22817900
84	Phosphorylation	DDGSPSSSSSSSSSS CCCCCCCCCCCCCCC	38.28	-
85	Phosphorylation	DGSPSSSSSSSSSSS CCCCCCCCCCCCCCC	35.87	-
86	Phosphorylation	GSPSSSSSSSSSSSS CCCCCCCCCCCCCCC	35.87	-
87	Phosphorylation	SPSSSSSSSSSSSSF CCCCCCCCCCCCCCC	35.87	-
117	Ubiquitination	SSRVSPSKSTSNITK CCCCCCCCCCCCHHH	62.22	-
167	Ubiquitination	IQQNIQYKRCLKNEN HHHHHCHHHHHCCCC	21.91	-
176	Phosphorylation	CLKNENCSIVRINRN HHCCCCCEEEEECCC	35.38	24719451
191	Acetylation	RCQQCRFKKCLSVGM CCCCCCCHHHCCCCC	24.19	17996965
192	Acetylation	CQQCRFKKCLSVGMS CCCCCCHHHCCCCCC	37.38	17996965
274	Phosphorylation	SQFPQQLTPPRSPSP CCCCCCCCCCCCCCC	27.23	-
278	Phosphorylation	QQLTPPRSPSPEPTV CCCCCCCCCCCCCCH	35.19	25850435
280	Phosphorylation	LTPPRSPSPEPTVED CCCCCCCCCCCCHHH	43.04	25850435
284	Phosphorylation	RSPSPEPTVEDVISQ CCCCCCCCHHHHHHH	34.56	27251275
306	Ubiquitination	IFTYAHDKLGSSPGN HHHHHHHHHCCCCCC	44.90	-
309	Phosphorylation	YAHDKLGSSPGNFNA HHHHHHCCCCCCCCC	43.74	27732954
310	Phosphorylation	AHDKLGSSPGNFNAN HHHHHCCCCCCCCCC	34.72	25159151
320	Phosphorylation	NFNANHASGSPPATT CCCCCCCCCCCCCCC	32.05	28985074
322	Phosphorylation	NANHASGSPPATTPH CCCCCCCCCCCCCCC	25.80	25159151
326	Phosphorylation	ASGSPPATTPHRWEN CCCCCCCCCCCCHHH	46.78	23312004
327	Phosphorylation	SGSPPATTPHRWENQ CCCCCCCCCCCHHHC	21.14	23312004
394	Phosphorylation	RLCPTHVYAAPEGKA CCCCCEEEECCCCCC	6.88	27642862
400	Ubiquitination	VYAAPEGKAPANSPR EEECCCCCCCCCCCC	49.92	24415752
400	Acetylation	VYAAPEGKAPANSPR EEECCCCCCCCCCCC	49.92	24415752
455	Ubiquitination	REVVEFAKHIPGFRD HHHHHHHHHCCCCCC	47.60	21906983
470	Phosphorylation	LSQHDQVTLLKAGTF CCCCCCEEHHHCCCH	22.27	22468782
486	Phosphorylation	VLMVRFASLFNVKDQ EEEEEHHHHCCCCCC	30.68	23532336
576	Ubiquitination	ALRALVLKNRPLETS HHHHHHHHCCCCCHH	43.35	21906983
587	Ubiquitination	LETSRFTKLLLKLPD CCHHHHHHHHHHCCC	34.13	-
591	Ubiquitination	RFTKLLLKLPDLRTL HHHHHHHHCCCHHHH	58.92	24415752
591	Acetylation	RFTKLLLKLPDLRTL HHHHHHHHCCCHHHH	58.92	24415752
597	Phosphorylation	LKLPDLRTLNNMHSE HHCCCHHHHCCCCCC	40.93	26074081
603	Phosphorylation	RTLNNMHSEKLLSFR HHHCCCCCCCHHHEE	26.17	26074081
605	Ubiquitination	LNNMHSEKLLSFRVD HCCCCCCCHHHEEEC	58.71	-
608	Phosphorylation	MHSEKLLSFRVDAQ- CCCCCHHHEEECCC-	22.80	24719451

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
55	S	Phosphorylation	Kinase	GSK3B	P49841	PSP
59	S	Phosphorylation	Kinase	GSK3B	P49841	PSP
274	T	Phosphorylation	Kinase	CDK1	P06493	Uniprot
-	K	Ubiquitination	E3 ubiquitin ligase	HUWE1	Q7Z6Z7	PMID:20534529

Functions of PTM Sites

Oops, there are no descriptions of PTM sites of NR1D1_HUMAN !!

Disease-associated PTM Sites based on SAP

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

Oops, there are no SNP-PTM records of NR1D1_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
HUWE1_HUMAN	HUWE1	physical	20534529
MYCB2_HUMAN	MYCBP2	physical	20534529
HDAC3_HUMAN	HDAC3	physical	20534529
NCOR1_HUMAN	NCOR1	physical	15604093
A4_HUMAN	APP	physical	21832049
NCOR2_HUMAN	NCOR2	physical	16219912
C1D_HUMAN	C1D	physical	9405624
NR2E3_HUMAN	NR2E3	physical	25703721

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

Phosphorylation

"Large-scale characterization of HeLa cell nuclear phosphoproteins.";
Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J.,Li J., Cohn M.A., Cantley L.C., Gygi S.P.;
Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004).
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-23, AND MASSSPECTROMETRY.
PubMed: 15302935