dbPTM

SIR1_MOUSE - PTM Information in dbPTM

Basic Information of Protein

Overview of Protein Modification Sites with Functional and Structural Information
UniProt ID	SIR1_MOUSE
UniProt AC	Q923E4
Protein Name	NAD-dependent protein deacetylase sirtuin-1
Gene Name	Sirt1
Organism	Mus musculus (Mouse).
Sequence Length	737
Subcellular Localization	Nucleus, PML body . Cytoplasm . Nucleus . Colocalizes in the nucleus with XBP1 isoform 2. Recruited to the nuclear bodies via its interaction with PML. Colocalized with APEX1 in the nucleus. May be found in nucleolus, nuclear euchromatin, heterochrom
Protein Description	NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metabolism, apoptosis and autophagy. Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1. Deacetylates FOXO1, which increases its DNA binding ability and enhances its transcriptional activity leading to increased gluconeogenesis in liver. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A-mediated transcription. Required for the repression of ESRRG by CREBZF. Modulates AP-1 transcription factor activity. Deacetylates NR1H3 AND NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates ACSS2 leading to its activation, and HMGCS1. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insulin-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-537' and 'Lys-540' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1-dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transactivation and contributes to its stability. Deacetylates MECOM/EVI1. Deacetylates PML at 'Lys-487' and this deacetylation promotes PML control of PER2 nuclear localization. During the neurogenic transition, repress selective NOTCH1-target genes through histone deacetylation in a BCL6-dependent manner and leading to neuronal differentiation. Regulates the circadian expression of several core clock genes, including ARNTL/BMAL1, RORC, PER2 and CRY1 and plays a critical role in maintaining a controlled rhythmicity in histone acetylation, thereby contributing to circadian chromatin remodeling. Deacetylates ARNTL/BMAL1 and histones at the circadian gene promoters in order to facilitate repression by inhibitory components of the circadian oscillator. Deacetylates PER2, facilitating its ubiquitination and degradation by the proteosome. Protects cardiomyocytes against palmitate-induced apoptosis. [PubMed: 11250901]
Protein Sequence	MADEVALALQAAGSPSAAAAMEAASQPADEPLRKRPRRDGPGLGRSPGEPSAAVAPAAAGCEAASAAAPAALWREAAGAAASAEREAPATAVAGDGDNGSGLRREPRAADDFDDDEGEEEDEAAAAAAAAAIGYRDNLLLTDGLLTNGFHSCESDDDDRTSHASSSDWTPRPRIGPYTFVQQHLMIGTDPRTILKDLLPETIPPPELDDMTLWQIVINILSEPPKRKKRKDINTIEDAVKLLQECKKIIVLTGAGVSVSCGIPDFRSRDGIYARLAVDFPDLPDPQAMFDIEYFRKDPRPFFKFAKEIYPGQFQPSLCHKFIALSDKEGKLLRNYTQNIDTLEQVAGIQRILQCHGSFATASCLICKYKVDCEAVRGDIFNQVVPRCPRCPADEPLAIMKPEIVFFGENLPEQFHRAMKYDKDEVDLLIVIGSSLKVRPVALIPSSIPHEVPQILINREPLPHLHFDVELLGDCDVIINELCHRLGGEYAKLCCNPVKLSEITEKPPRPQKELVHLSELPPTPLHISEDSSSPERTVPQDSSVIATLVDQATNNNVNDLEVSESSCVEEKPQEVQTSRNVENINVENPDFKAVGSSTADKNERTSVAETVRKCWPNRLAKEQISKRLEGNQYLFVPPNRYIFHGAEVYSDSEDDVLSSSSCGSNSDSGTCQSPSLEEPLEDESEIEEFYNGLEDDTERPECAGGSGFGADGGDQEVVNEAIATRQELTDVNYPSDKS

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
2	Acetylation	------MADEVALAL ------CHHHHHHHH	22.98	-
14	Phosphorylation	LALQAAGSPSAAAAM HHHHHCCCHHHHHHH	15.79	26824392
16	Phosphorylation	LQAAGSPSAAAAMEA HHHCCCHHHHHHHHH	32.03	25619855
25	Phosphorylation	AAAMEAASQPADEPL HHHHHHHHCCCCCCH	43.68	25619855
46	Phosphorylation	DGPGLGRSPGEPSAA CCCCCCCCCCCCCCC	35.14	22942356
51	Phosphorylation	GRSPGEPSAAVAPAA CCCCCCCCCCCCHHH	25.26	25266776
65	Phosphorylation	AAGCEAASAAAPAAL HHCHHHHHHHHHHHH	26.03	24759943
146	Phosphorylation	LLTDGLLTNGFHSCE EECCCCCCCCCCCCC	38.04	21183079
151	Phosphorylation	LLTNGFHSCESDDDD CCCCCCCCCCCCCCC	19.81	21183079
154	Phosphorylation	NGFHSCESDDDDRTS CCCCCCCCCCCCCCC	51.14	19680552
160	Phosphorylation	ESDDDDRTSHASSSD CCCCCCCCCCCCCCC	31.68	21183079
161	Phosphorylation	SDDDDRTSHASSSDW CCCCCCCCCCCCCCC	20.25	21183079
164	Phosphorylation	DDRTSHASSSDWTPR CCCCCCCCCCCCCCC	25.58	21183079
165	Phosphorylation	DRTSHASSSDWTPRP CCCCCCCCCCCCCCC	32.85	21183079
166	Phosphorylation	RTSHASSSDWTPRPR CCCCCCCCCCCCCCC	34.37	21183079
169	Phosphorylation	HASSSDWTPRPRIGP CCCCCCCCCCCCCCC	17.89	21183079
230	Acetylation	PPKRKKRKDINTIED CCCCCCCCCCCHHHH	72.36	28923965
369	Acetylation	SCLICKYKVDCEAVR EEEEEEEEECHHHHC	19.66	28923965
387	S-nitrosylation	FNQVVPRCPRCPADE HHCCCCCCCCCCCCC	1.72	20972425
387	S-nitrosocysteine	FNQVVPRCPRCPADE HHCCCCCCCCCCCCC	1.72	-
390	S-nitrosylation	VVPRCPRCPADEPLA CCCCCCCCCCCCCCE	1.65	20972425
390	S-nitrosocysteine	VVPRCPRCPADEPLA CCCCCCCCCCCCCCE	1.65	-
422	Acetylation	HRAMKYDKDEVDLLI HHHHCCCHHHCCEEE	53.34	28923965
434	Phosphorylation	LLIVIGSSLKVRPVA EEEEECCCCCEEEEE	27.31	22195961
505	Acetylation	KLSEITEKPPRPQKE EHHHHCCCCCCCCHH	52.23	28923965
517	Phosphorylation	QKELVHLSELPPTPL CHHEEEHHHCCCCCC	23.39	25293948
522	Phosphorylation	HLSELPPTPLHISED EHHHCCCCCCCCCCC	36.22	22817900
527	Phosphorylation	PPTPLHISEDSSSPE CCCCCCCCCCCCCCC	25.30	21082442
530	Phosphorylation	PLHISEDSSSPERTV CCCCCCCCCCCCCCC	28.76	21082442
531	Phosphorylation	LHISEDSSSPERTVP CCCCCCCCCCCCCCC	63.33	21082442
532	Phosphorylation	HISEDSSSPERTVPQ CCCCCCCCCCCCCCC	34.43	21659605
536	Phosphorylation	DSSSPERTVPQDSSV CCCCCCCCCCCCCHH	34.57	-
600	Acetylation	VGSSTADKNERTSVA ECCCCCCCCCCCCHH	59.24	28923965
604	Phosphorylation	TADKNERTSVAETVR CCCCCCCCCHHHHHH	22.75	23375375
605	Phosphorylation	ADKNERTSVAETVRK CCCCCCCCHHHHHHH	26.08	28833060
609	Phosphorylation	ERTSVAETVRKCWPN CCCCHHHHHHHHHCC	18.84	23375375
649	Phosphorylation	FHGAEVYSDSEDDVL EECEEEECCCCCCCC	39.58	19680552
651	Phosphorylation	GAEVYSDSEDDVLSS CEEEECCCCCCCCCC	36.66	19680552
683	Phosphorylation	EEPLEDESEIEEFYN CCCCCCHHHHHHHHH	57.08	19680552
728	Phosphorylation	IATRQELTDVNYPSD HHHHHHHHCCCCCCC	36.83	28066266
732	Phosphorylation	QELTDVNYPSDKS-- HHHHCCCCCCCCC--	12.17	28066266
734	Phosphorylation	LTDVNYPSDKS---- HHCCCCCCCCC----	47.51	21149613
737	Phosphorylation	VNYPSDKS------- CCCCCCCC-------	50.90	21149613

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
46	S	Phosphorylation	Kinase	JNK1	Q91Y86	PSP
154	S	Phosphorylation	Kinase	CSNK2A1	P68400	GPS
164	S	Phosphorylation	Kinase	CSNK2A1	Q60737	GPS
434	S	Phosphorylation	Kinase	PKACA	P17612	PSP
434	S	Phosphorylation	Kinase	PKACA	P05132	PSP
522	T	Phosphorylation	Kinase	DYRK1A	Q13627	PSP
522	T	Phosphorylation	Kinase	DYRK1A	Q61214	Uniprot
522	T	Phosphorylation	Kinase	DYRK3	O43781	PSP
522	T	Phosphorylation	Kinase	DYRK3	Q922Y0	Uniprot
522	T	Phosphorylation	Kinase	MAPK8	Q91Y86	Uniprot
649	S	Phosphorylation	Kinase	CSNK2A1	P68400	GPS
649	S	Phosphorylation	Kinase	CAMK2B	P28652	GPS
649	S	Phosphorylation	Kinase	CAMK2	-	Uniprot
651	S	Phosphorylation	Kinase	CSNK2A1	P68400	GPS
651	S	Phosphorylation	Kinase	CAMK2	-	Uniprot
683	S	Phosphorylation	Kinase	CSNK2A1	P68400	GPS

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Reference
46	S	Acetylation	20167603
Phosphorylation by mammalian target of rapamycin complex 1 (mTORC1) at Ser-46 inhibits deacetylation activity.
46	S	Phosphorylation	20167603
Phosphorylation by MAPK8/JNK1 at Ser-46 and Thr-522 leads to increased nuclear localization and enzymatic activity.
46	S	Phosphorylation	20167603
Phosphorylation by mammalian target of rapamycin complex 1 (mTORC1) at Ser-46 inhibits deacetylation activity.
230	K	Acetylation	17197703
Autodeacetylation at Lys-230 promotes its protein deacetylase activity.
522	T	Acetylation	20167603
Phosphorylation at Thr-522 by DYRK1A and DYRK3 activates deacetylase activity and promotes cell survival.
522	T	Phosphorylation	20167603
Phosphorylation at Thr-522 by DYRK1A and DYRK3 activates deacetylase activity and promotes cell survival.
522	T	Phosphorylation	20167603
Phosphorylation by MAPK8/JNK1 at Ser-46 and Thr-522 leads to increased nuclear localization and enzymatic activity.

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 SIR1_MOUSE !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
TF65_MOUSE	Rela	physical	21454709
EP300_MOUSE	Ep300	physical	21454709
ERR1_MOUSE	Esrra	physical	20484414
NR0B2_MOUSE	Nr0b2	physical	20375098
HNF1A_MOUSE	Hnf1a	physical	21176092
PAX3_MOUSE	Pax3	physical	21169561
HES1_MOUSE	Hes1	physical	21169561
NGN2_MOUSE	Neurog2	physical	21169561
NR0B2_MOUSE	Nr0b2	physical	21081708
ACACA_MOUSE	Acaca	physical	19343720
PRGC1_MOUSE	Ppargc1a	physical	15744310
HNF4A_MOUSE	Hnf4a	physical	15744310
KAT8_MOUSE	Kat8	physical	22586264
KAT5_MOUSE	Kat5	physical	22586264
MECP2_MOUSE	Mecp2	physical	22677942
NCOR2_MOUSE	Ncor2	physical	15175761
CLOCK_MOUSE	Clock	physical	18662546
BMAL1_MOUSE	Arntl	physical	18662546
PER2_MOUSE	Per2	physical	18662546
IRS2_HUMAN	IRS2	physical	17901049
P53_HUMAN	TP53	physical	19680552
DYRK3_MOUSE	Dyrk3	physical	20167603
DYR1A_HUMAN	DYRK1A	physical	20167603
DYRK3_HUMAN	DYRK3	physical	20167603
DYR1A_MOUSE	Dyrk1a	physical	20167603
P53_HUMAN	TP53	physical	20167603
FOXO1_MOUSE	Foxo1	physical	22514318
NECD_MOUSE	Ndn	physical	22514318
CBX5_MOUSE	Cbx5	physical	28059589

Drug and Disease Associations

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

Regulatory Network of SIR1_MOUSE

Related Literatures of Post-Translational Modification

Phosphorylation
Reference	PubMed
"CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylaseactivity and cellular response to DNA-damage."; Kang H., Jung J.W., Kim M.K., Chung J.H.; PLoS ONE 4:E6611-E6611(2009). Cited for: PHOSPHORYLATION AT SER-649, AND MUTAGENESIS OF SER-154; SER-649;SER-651 AND SER-683.	19680552 [Abstract]
"DYRK1A and DYRK3 promote cell survival through phosphorylation andactivation of SIRT1."; Guo X., Williams J.G., Schug T.T., Li X.; J. Biol. Chem. 285:13223-13232(2010). Cited for: PHOSPHORYLATION AT THR-522, AND MUTAGENEIS OF THR-522.	20167603 [Abstract]
S-nitrosylation
Reference	PubMed
"GAPDH mediates nitrosylation of nuclear proteins."; Kornberg M.D., Sen N., Hara M.R., Juluri K.R., Nguyen J.V.,Snowman A.M., Law L., Hester L.D., Snyder S.H.; Nat. Cell Biol. 12:1094-1100(2010). Cited for: S-NITROSYLATION AT CYS-387 AND CYS-390, AND MUTAGENESIS OF CYS-363;CYS-366; CYS-387 AND CYS-390.	20972425 [Abstract]

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