NMNA2_MOUSE
ID NMNA2_MOUSE Reviewed; 307 AA.
AC Q8BNJ3;
DT 10-MAY-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 {ECO:0000305};
DE Short=NMN/NaMN adenylyltransferase 2;
DE EC=2.7.7.1 {ECO:0000250|UniProtKB:Q9BZQ4};
DE EC=2.7.7.18 {ECO:0000250|UniProtKB:Q9BZQ4};
DE AltName: Full=Nicotinamide mononucleotide adenylyltransferase 2;
DE Short=NMN adenylyltransferase 2;
DE AltName: Full=Nicotinate-nucleotide adenylyltransferase 2;
DE Short=NaMN adenylyltransferase 2;
DE AltName: Full=Protein bloated bladder {ECO:0000303|PubMed:23082226};
DE Short=Blad {ECO:0000303|PubMed:23082226};
GN Name=Nmnat2 {ECO:0000312|MGI:MGI:2444155};
GN Synonyms=Kiaa0479 {ECO:0000303|PubMed:14621295};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14621295; DOI=10.1093/dnares/10.4.167;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: III.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 10:167-180(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP FUNCTION, AND PROTEIN DEGRADATION.
RX PubMed=20126265; DOI=10.1371/journal.pbio.1000300;
RA Gilley J., Coleman M.P.;
RT "Endogenous Nmnat2 is an essential survival factor for maintenance of
RT healthy axons.";
RL PLoS Biol. 8:E1000300-E1000300(2010).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23082226; DOI=10.1371/journal.pone.0047869;
RA Hicks A.N., Lorenzetti D., Gilley J., Lu B., Andersson K.E., Miligan C.,
RA Overbeek P.A., Oppenheim R., Bishop C.E.;
RT "Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) regulates axon
RT integrity in the mouse embryo.";
RL PLoS ONE 7:E47869-E47869(2012).
RN [5]
RP PROTEIN DEGRADATION.
RX PubMed=23665224; DOI=10.1016/j.celrep.2013.04.013;
RA Babetto E., Beirowski B., Russler E.V., Milbrandt J., DiAntonio A.;
RT "The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction.";
RL Cell Rep. 3:1422-1429(2013).
RN [6]
RP PROTEIN DEGRADATION, UBIQUITINATION, SUBCELLULAR LOCATION, PALMITOYLATION
RP AT CYS-164 AND CYS-165, AND MUTAGENESIS OF LYS-151; LYS-155; ARG-162;
RP 164-CYS-CYS-165; ARG-167 AND ARG-172.
RX PubMed=23610559; DOI=10.1371/journal.pbio.1001539;
RA Milde S., Gilley J., Coleman M.P.;
RT "Subcellular localization determines the stability and axon protective
RT capacity of axon survival factor Nmnat2.";
RL PLoS Biol. 11:E1001539-E1001539(2013).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=25818290; DOI=10.1016/j.celrep.2015.02.060;
RA Gilley J., Orsomando G., Nascimento-Ferreira I., Coleman M.P.;
RT "Absence of SARM1 rescues development and survival of NMNAT2-deficient
RT axons.";
RL Cell Rep. 10:1974-1981(2015).
CC -!- FUNCTION: Nicotinamide/nicotinate-nucleotide adenylyltransferase that
CC acts as an axon maintenance factor (PubMed:20126265, PubMed:23082226).
CC Catalyzes the formation of NAD(+) from nicotinamide mononucleotide
CC (NMN) and ATP (By similarity). Can also use the deamidated form;
CC nicotinic acid mononucleotide (NaMN) as substrate but with a lower
CC efficiency (By similarity). Cannot use triazofurin monophosphate (TrMP)
CC as substrate (By similarity). Also catalyzes the reverse reaction, i.e.
CC the pyrophosphorolytic cleavage of NAD(+) (By similarity). For the
CC pyrophosphorolytic activity prefers NAD(+), NADH and NaAD as substrates
CC and degrades nicotinic acid adenine dinucleotide phosphate (NHD) less
CC effectively (By similarity). Fails to cleave phosphorylated
CC dinucleotides NADP(+), NADPH and NaADP(+) (By similarity). Axon
CC survival factor required for the maintenance of healthy axons: acts by
CC delaying Wallerian axon degeneration, an evolutionarily conserved
CC process that drives the loss of damaged axons (PubMed:20126265,
CC PubMed:23082226, PubMed:25818290$). {ECO:0000250|UniProtKB:Q9BZQ4,
CC ECO:0000269|PubMed:20126265, ECO:0000269|PubMed:23082226,
CC ECO:0000269|PubMed:25818290}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + beta-nicotinamide D-ribonucleotide + H(+) = diphosphate
CC + NAD(+); Xref=Rhea:RHEA:21360, ChEBI:CHEBI:14649, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:57540; EC=2.7.7.1;
CC Evidence={ECO:0000250|UniProtKB:Q9BZQ4};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21361;
CC Evidence={ECO:0000250|UniProtKB:Q9BZQ4};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:21362;
CC Evidence={ECO:0000250|UniProtKB:Q9BZQ4};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H(+) + nicotinate beta-D-ribonucleotide = deamido-NAD(+)
CC + diphosphate; Xref=Rhea:RHEA:22860, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:57502,
CC ChEBI:CHEBI:58437; EC=2.7.7.18;
CC Evidence={ECO:0000250|UniProtKB:Q9BZQ4};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22861;
CC Evidence={ECO:0000250|UniProtKB:Q9BZQ4};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:22862;
CC Evidence={ECO:0000250|UniProtKB:Q9BZQ4};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:Q9BZQ4};
CC Note=Divalent metal cations. Mg(2+) confers the highest activity.
CC {ECO:0000250|UniProtKB:Q9BZQ4};
CC -!- ACTIVITY REGULATION: Inhibited by P1-(adenosine-5')-P3-(nicotinamide-
CC riboside-5')-triphosphate (Np3AD) and P1-(adenosine-5')-P4-
CC (nicotinamide-riboside-5')-tetraphosphate (Np4AD).
CC {ECO:0000250|UniProtKB:Q9BZQ4}.
CC -!- PATHWAY: Cofactor biosynthesis; NAD(+) biosynthesis; NAD(+) from
CC nicotinamide D-ribonucleotide: step 1/1.
CC {ECO:0000250|UniProtKB:Q9BZQ4}.
CC -!- PATHWAY: Cofactor biosynthesis; NAD(+) biosynthesis; deamido-NAD(+)
CC from nicotinate D-ribonucleotide: step 1/1.
CC {ECO:0000250|UniProtKB:Q9BZQ4}.
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:Q9BZQ4}.
CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane
CC {ECO:0000269|PubMed:23610559}; Lipid-anchor
CC {ECO:0000269|PubMed:23610559}. Cytoplasmic vesicle membrane; Lipid-
CC anchor {ECO:0000269|PubMed:23610559}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q9BZQ4}. Cell projection, axon
CC {ECO:0000269|PubMed:23610559}. Note=Delivered to axons with Golgi-
CC derived cytoplasmic vesicles. {ECO:0000269|PubMed:23610559}.
CC -!- TISSUE SPECIFICITY: Expressed predominantly in the brain and nervous
CC system. {ECO:0000269|PubMed:23082226}.
CC -!- PTM: Degraded in response to injured neurite (PubMed:20126265,
CC PubMed:23665224, PubMed:23610559). Degradation is probably caused by
CC ubiquitination by MYCBP2 (PubMed:23665224, PubMed:23610559).
CC Ubiquitinated on threonine and/or serine residues by MYCBP2;
CC consequences of threonine and/or serine ubiquitination are however
CC unclear (By similarity). {ECO:0000250|UniProtKB:Q9BZQ4,
CC ECO:0000269|PubMed:20126265, ECO:0000269|PubMed:23610559,
CC ECO:0000269|PubMed:23665224}.
CC -!- PTM: Palmitoylated; palmitoylation is required for membrane
CC association. {ECO:0000269|PubMed:23610559}.
CC -!- DISRUPTION PHENOTYPE: Perinatal lethality (PubMed:23082226). Mice show
CC a greatly distended bladder, underdeveloped diaphragm and a reduction
CC in total skeletal muscle mass (PubMed:23082226). Defects are caused by
CC defects in innervation of major organs and tissues (PubMed:23082226).
CC Mice lacking both Sarm1 and Nmnat2 are viable and survive: Sarm1
CC deficiency corrects axon outgrowth in mice lacking Nmnat2,
CC independently of NMNAT metabolites, preventing perinatal lethality
CC (PubMed:25818290). {ECO:0000269|PubMed:23082226,
CC ECO:0000269|PubMed:25818290}.
CC -!- SIMILARITY: Belongs to the eukaryotic NMN adenylyltransferase family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC97965.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AK129155; BAC97965.1; ALT_FRAME; mRNA.
DR EMBL; AK083532; BAC38943.1; -; mRNA.
DR CCDS; CCDS15368.1; -.
DR RefSeq; NP_780669.1; NM_175460.3.
DR AlphaFoldDB; Q8BNJ3; -.
DR SMR; Q8BNJ3; -.
DR STRING; 10090.ENSMUSP00000041110; -.
DR iPTMnet; Q8BNJ3; -.
DR PhosphoSitePlus; Q8BNJ3; -.
DR SwissPalm; Q8BNJ3; -.
DR PaxDb; Q8BNJ3; -.
DR PRIDE; Q8BNJ3; -.
DR ProteomicsDB; 293694; -.
DR Antibodypedia; 2924; 161 antibodies from 22 providers.
DR DNASU; 226518; -.
DR Ensembl; ENSMUST00000043313; ENSMUSP00000041110; ENSMUSG00000042751.
DR GeneID; 226518; -.
DR KEGG; mmu:226518; -.
DR UCSC; uc007czq.1; mouse.
DR CTD; 23057; -.
DR MGI; MGI:2444155; Nmnat2.
DR VEuPathDB; HostDB:ENSMUSG00000042751; -.
DR eggNOG; KOG3199; Eukaryota.
DR GeneTree; ENSGT00950000183179; -.
DR HOGENOM; CLU_033366_1_0_1; -.
DR InParanoid; Q8BNJ3; -.
DR OMA; VNHPMSI; -.
DR OrthoDB; 1308027at2759; -.
DR PhylomeDB; Q8BNJ3; -.
DR TreeFam; TF315035; -.
DR BRENDA; 2.7.7.1; 3474.
DR BRENDA; 2.7.7.18; 3474.
DR Reactome; R-MMU-196807; Nicotinate metabolism.
DR UniPathway; UPA00253; UER00332.
DR UniPathway; UPA00253; UER00600.
DR BioGRID-ORCS; 226518; 0 hits in 72 CRISPR screens.
DR ChiTaRS; Nmnat2; mouse.
DR PRO; PR:Q8BNJ3; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q8BNJ3; protein.
DR Bgee; ENSMUSG00000042751; Expressed in medial dorsal nucleus of thalamus and 163 other tissues.
DR ExpressionAtlas; Q8BNJ3; baseline and differential.
DR Genevisible; Q8BNJ3; MM.
DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005794; C:Golgi apparatus; IDA:MGI.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005770; C:late endosome; IDA:MGI.
DR GO; GO:0045202; C:synapse; IDA:MGI.
DR GO; GO:0005802; C:trans-Golgi network; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0000309; F:nicotinamide-nucleotide adenylyltransferase activity; IBA:GO_Central.
DR GO; GO:0004515; F:nicotinate-nucleotide adenylyltransferase activity; ISO:MGI.
DR GO; GO:0009435; P:NAD biosynthetic process; ISO:MGI.
DR CDD; cd09286; NMNAT_Eukarya; 1.
DR Gene3D; 3.40.50.620; -; 1.
DR InterPro; IPR004821; Cyt_trans-like.
DR InterPro; IPR045094; NMNAT_euk.
DR InterPro; IPR014729; Rossmann-like_a/b/a_fold.
DR Pfam; PF01467; CTP_transf_like; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Cell projection; Cytoplasm; Cytoplasmic vesicle;
KW Golgi apparatus; Lipoprotein; Membrane; NAD; Nucleotide-binding;
KW Nucleotidyltransferase; Palmitate; Pyridine nucleotide biosynthesis;
KW Reference proteome; Transferase; Ubl conjugation.
FT CHAIN 1..307
FT /note="Nicotinamide/nicotinic acid mononucleotide
FT adenylyltransferase 2"
FT /id="PRO_0000135015"
FT BINDING 15..17
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q96T66"
FT BINDING 24
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q96T66"
FT BINDING 55..57
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q96T66"
FT BINDING 92..95
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q96T66"
FT BINDING 200..202
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q96T66"
FT BINDING 212..213
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q96T66"
FT BINDING 271..274
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:Q96T66"
FT LIPID 164
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:23610559"
FT LIPID 165
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000269|PubMed:23610559"
FT MUTAGEN 151
FT /note="K->A: Impaired membrane association in neurons; when
FT associated with A-155; A-162; A-167 and A-172."
FT MUTAGEN 155
FT /note="K->A: Impaired membrane association in neurons; when
FT associated with A-151; A-162; A-167 and A-172."
FT MUTAGEN 162
FT /note="R->A: Impaired membrane association in neurons; when
FT associated with A-151; A-155; A-167 and A-172."
FT MUTAGEN 164..165
FT /note="CC->SS: Abolished palmitoylation and membrane
FT association in neurons."
FT /evidence="ECO:0000269|PubMed:23610559"
FT MUTAGEN 167
FT /note="R->A: Impaired membrane association in neurons; when
FT associated with A-151; A-155; A-162 and A-172."
FT MUTAGEN 172
FT /note="R->A: Impaired membrane association in neurons; when
FT associated with A-151; A-155; A-162 and A-167."
SQ SEQUENCE 307 AA; 34505 MW; B9B4902D3EE03DC6 CRC64;
MTETTKTHVI LLACGSFNPI TKGHIQMFER ARDYLHKTGR FIVIGGIVSP VHDSYGKQGL
VSSRHRLIMC QLAVQNSDWI RVDPWECYQD TWQTTCSVLE HHRDLMKRVT GCILSNVNTP
SMTPVIGQPQ HENTQPIYQN SNVPTKPTAA KILGKVGESL SRICCVRPPV ERFTFVDENA
NLGTVMRYEE IELRILLLCG SDLLESFCIP GLWNEADMEV IVGDFGIVVV PRDAADTDRI
MNHSSILRKY KNNIMVVKDD INHPMSVVSS TKSRLALQHG DGHVVDYLSQ PVIDYILKSQ
LYINASG
