NPAS2_HUMAN - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: NPAS2_HUMAN
• UniProt AC: Q99743
• Protein Name: Neuronal PAS domain-containing protein 2
• Gene Name: NPAS2
• Organism: Homo sapiens (Human).
• Sequence Length: 824
• Subcellular Localization: Nucleus .
• Protein Description: Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. The NPAS2-ARNTL/BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. NPAS2 plays an important role in sleep homeostasis and in maintaining circadian behaviors in normal light/dark and feeding conditions and in the effective synchronization of feeding behavior with scheduled food availability. Regulates the gene transcription of key metabolic pathways in the liver and is involved in DNA damage response by regulating several cell cycle and DNA repair genes..
• Protein Sequence: MDEDEKDRAKRASRNKSEKKRRDQFNVLIKELSSMLPGNTRKMDKTTVLEKVIGFLQKHNEVSAQTEICDIQQDWKPSFLSNEEFTQLMLEALDGFIIAVTTDGSIIYVSDSITPLLGHLPSDVMDQNLLNFLPEQEHSEVYKILSSHMLVTDSPSPEYLKSDSDLEFYCHLLRGSLNPKEFPTYEYIKFVGNFRSYNNVPSPSCNGFDNTLSRPCRVPLGKEVCFIATVRLATPQFLKEMCIVDEPLEEFTSRHSLEWKFLFLDHRAPPIIGYLPFEVLGTSGYDYYHIDDLELLARCHQHLMQFGKGKSCCYRFLTKGQQWIWLQTHYYITYHQWNSKPEFIVCTHSVVSYADVRVERRQELALEDPPSEALHSSALKDKGSSLEPRQHFNTLDVGASGLNTSHSPSASSRSSHKSSHTAMSEPTSTPTKLMAEASTPALPRSATLPQELPVPGLSQAATMPAPLPSPSSCDLTQQLLPQTVLQSTPAPMAQFSAQFSMFQTIKDQLEQRTRILQANIRWQQEELHKIQEQLCLVQDSNVQMFLQQPAVSLSFSSTQRPEAQQQLQQRSAAVTQPQLGAGPQLPGQISSAQVTSQHLLRESSVISTQGPKPMRSSQLMQSSGRSGSSLVSPFSSATAALPPSLNLTTPASTSQDASQCQPSPDFSHDRQLRLLLSQPIQPMMPGSCDARQPSEVSRTGRQVKYAQSQTVFQNPDAHPANSSSAPMPVLLMGQAVLHPSFPASQPSPLQPAQARQQPPQHYLQVQAPTSLHSEQQDSLLLSTYSQQPGTLGYPQPPPAQPQPLRPPRRVSSLSESSGLQQPPR

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
13	Phosphorylation	KDRAKRASRNKSEKK HHHHHHHHCCHHHHH	40.18	29038488
17	Phosphorylation	KRASRNKSEKKRRDQ HHHHCCHHHHHHHHH	59.19	29038488
33	Phosphorylation	NVLIKELSSMLPGNT HHHHHHHHHCCCCCC	18.13	26437602
34	Phosphorylation	VLIKELSSMLPGNTR HHHHHHHHCCCCCCC	36.64	26437602
40	Phosphorylation	SSMLPGNTRKMDKTT HHCCCCCCCCCCHHH	37.27	26437602
47	Phosphorylation	TRKMDKTTVLEKVIG CCCCCHHHHHHHHHH	28.91	-
156	Phosphorylation	MLVTDSPSPEYLKSD CEECCCCCHHHHCCC	34.02	21815630
202	Phosphorylation	RSYNNVPSPSCNGFD CCCCCCCCCCCCCCC	25.76	23898821
204	Phosphorylation	YNNVPSPSCNGFDNT CCCCCCCCCCCCCCC	25.26	23898821
311	Phosphorylation	MQFGKGKSCCYRFLT HHCCCCCCHHHHHHC	20.35	-
384	Phosphorylation	SALKDKGSSLEPRQH HHHCCCCCCCCCCCC	37.17	27251275
429	Phosphorylation	AMSEPTSTPTKLMAE CCCCCCCCCCHHHHH	37.14	-
603	Phosphorylation	SQHLLRESSVISTQG HHHHHHHCCCEECCC	24.38	-
677	Phosphorylation	RQLRLLLSQPIQPMM HHHHHHHCCCCCCCC	33.60	-
687	Phosphorylation	IQPMMPGSCDARQPS CCCCCCCCCCCCCCC	11.71	-
811	Phosphorylation	LRPPRRVSSLSESSG CCCCCCCCCCCCCCC	24.61	23312004
812	Phosphorylation	RPPRRVSSLSESSGL CCCCCCCCCCCCCCC	32.81	22210691
814	Phosphorylation	PRRVSSLSESSGLQQ CCCCCCCCCCCCCCC	37.06	22210691
816	Phosphorylation	RVSSLSESSGLQQPP CCCCCCCCCCCCCCC	26.74	23312004
817	Phosphorylation	VSSLSESSGLQQPPR CCCCCCCCCCCCCCC	39.20	23312004

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Oops, there are no upstream regulatory protein records of NPAS2_HUMAN !!

Functions of PTM Sites

Oops, there are no descriptions of PTM sites of NPAS2_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 NPAS2_HUMAN !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
NCOA3_HUMAN	NCOA3	physical	14645221
EP300_HUMAN	EP300	physical	14645221
KAT2B_HUMAN	KAT2B	physical	14645221
CBP_HUMAN	CREBBP	physical	14645221
BMAL1_HUMAN	ARNTL	physical	11439184
BMAL1_HUMAN	ARNTL	physical	9576906
HESX1_HUMAN	HESX1	physical	20211142
RHXF1_HUMAN	RHOXF1	physical	20211142
ZSCA1_HUMAN	ZSCAN1	physical	20211142
RL6_HUMAN	RPL6	physical	21988832
BMAL1_HUMAN	ARNTL	physical	24722188
BMAL2_HUMAN	ARNTL2	physical	24722188
CRX_HUMAN	CRX	physical	24722188
EFS_HUMAN	EFS	physical	24722188
HGS_HUMAN	HGS	physical	24722188
RASF7_HUMAN	RASSF7	physical	24722188
RORG_HUMAN	RORC	physical	23555304

Drug and Disease Associations

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