NMRL1_HUMAN
ID NMRL1_HUMAN Reviewed; 299 AA.
AC Q9HBL8;
DT 20-FEB-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 153.
DE RecName: Full=NmrA-like family domain-containing protein 1;
GN Name=NMRAL1; Synonyms=HSCARG;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Adrenal gland;
RA Xiao H., Song H., Gao G., Ren S., Chen Z., Han Z.;
RL Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA Myers R.M., Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin, and Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP FUNCTION, INTERACTION WITH ASS1, SUBCELLULAR LOCATION, INDUCTION, AND
RP REGION.
RX PubMed=18263583; DOI=10.1074/jbc.m708697200;
RA Zhao Y., Zhang J., Li H., Li Y., Ren J., Luo M., Zheng X.;
RT "An NADPH sensor protein (HSCARG) down-regulates nitric oxide synthesis by
RT association with argininosuccinate synthetase and is essential for
RT epithelial cell viability.";
RL J. Biol. Chem. 283:11004-11013(2008).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH NADP, FUNCTION,
RP HOMODIMERIZATION, INTERACTION WITH ASS1, AND SUBCELLULAR LOCATION.
RX PubMed=17496144; DOI=10.1073/pnas.0700480104;
RA Zheng X., Dai X., Zhao Y., Chen Q., Lu F., Yao D., Yu Q., Liu X., Zhang C.,
RA Gu X., Luo M.;
RT "Restructuring of the dinucleotide-binding fold in an NADP(H) sensor
RT protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:8809-8814(2007).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF MUTANT ALA-37, X-RAY
RP CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF MUTANT ALA-81, FUNCTION, SUBUNIT,
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF ARG-37; LYS-41; TYR-81 AND
RP LYS-133.
RX PubMed=19254724; DOI=10.1016/j.jmb.2009.02.049;
RA Dai X., Li Y., Meng G., Yao S., Zhao Y., Yu Q., Zhang J., Luo M., Zheng X.;
RT "NADPH is an allosteric regulator of HSCARG.";
RL J. Mol. Biol. 387:1277-1285(2009).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) IN COMPLEX WITH NIFLUMIC ACID.
RG Structural genomics consortium (SGC);
RT "Crystal structure of NMRA-like family domain containing protein 1 in
RT complex with niflumic acid.";
RL Submitted (AUG-2009) to the PDB data bank.
CC -!- FUNCTION: Redox sensor protein. Undergoes restructuring and subcellular
CC redistribution in response to changes in intracellular NADPH/NADP(+)
CC levels. At low NADPH concentrations the protein is found mainly as a
CC monomer, and binds argininosuccinate synthase (ASS1), the enzyme
CC involved in nitric oxide synthesis. Association with ASS1 impairs its
CC activity and reduces the production of nitric oxide, which subsecuently
CC prevents apoptosis. Under normal NADPH concentrations, the protein is
CC found as a dimer and hides the binding site for ASS1. The homodimer
CC binds one molecule of NADPH. Has higher affinity for NADPH than for
CC NADP(+). Binding to NADPH is necessary to form a stable dimer.
CC {ECO:0000269|PubMed:17496144, ECO:0000269|PubMed:18263583,
CC ECO:0000269|PubMed:19254724}.
CC -!- SUBUNIT: Homodimer. Interacts with ASS1. Interaction is enhanced by low
CC NADPH/NADP(+) ratios, which results in inhibition of ASS1 activity.
CC {ECO:0000269|PubMed:17496144, ECO:0000269|PubMed:18263583,
CC ECO:0000269|PubMed:19254724, ECO:0000269|Ref.8}.
CC -!- INTERACTION:
CC Q9HBL8; P00966: ASS1; NbExp=3; IntAct=EBI-2862643, EBI-536842;
CC Q9HBL8; Q9HBL8: NMRAL1; NbExp=2; IntAct=EBI-2862643, EBI-2862643;
CC Q9HBL8; Q96CV9: OPTN; NbExp=3; IntAct=EBI-2862643, EBI-748974;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, perinuclear region.
CC Nucleus. Note=Under normal redox growth conditions localizes in the
CC cytoplasm and perinuclear region. Nuclear localization is promoted by
CC increased intracellular nitric oxide and reduced NADPH/NADP(+) ratios.
CC -!- INDUCTION: By nitric oxide, cGMP and pro-inflammatory cytokines.
CC {ECO:0000269|PubMed:18263583}.
CC -!- MISCELLANEOUS: Reduced levels of NMRAL1 by RNAi increases nitric oxide
CC production and reduces cell viability. Overexpression of NMRAL1
CC increases cell viability.
CC -!- SIMILARITY: Belongs to the NmrA-type oxidoreductase family.
CC {ECO:0000305}.
CC -!- CAUTION: Lacks the conserved Tyr residue in the active site triad of
CC Ser-Tyr-Lys necessary for dehydrogenase activity, suggesting that it
CC has no oxidoreductase activity. {ECO:0000305}.
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DR EMBL; AF225419; AAG09721.1; -; mRNA.
DR EMBL; AC012676; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC007606; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC002927; AAH02927.1; -; mRNA.
DR EMBL; BC007364; AAH07364.1; -; mRNA.
DR CCDS; CCDS10516.1; -.
DR RefSeq; NP_001292070.1; NM_001305141.1.
DR RefSeq; NP_001292071.1; NM_001305142.1.
DR RefSeq; NP_065728.1; NM_020677.4.
DR PDB; 2EXX; X-ray; 2.40 A; A/B=1-299.
DR PDB; 2WM3; X-ray; 1.85 A; A=1-298.
DR PDB; 2WMD; X-ray; 2.00 A; A=1-298.
DR PDB; 3DXF; X-ray; 2.20 A; A/B=1-299.
DR PDB; 3E5M; X-ray; 2.70 A; A/B=1-299.
DR PDBsum; 2EXX; -.
DR PDBsum; 2WM3; -.
DR PDBsum; 2WMD; -.
DR PDBsum; 3DXF; -.
DR PDBsum; 3E5M; -.
DR AlphaFoldDB; Q9HBL8; -.
DR SMR; Q9HBL8; -.
DR BioGRID; 121509; 243.
DR DIP; DIP-60944N; -.
DR IntAct; Q9HBL8; 6.
DR STRING; 9606.ENSP00000458762; -.
DR BindingDB; Q9HBL8; -.
DR ChEMBL; CHEMBL4802017; -.
DR DrugBank; DB08784; 2-(4-CHLORO-PHENYLAMINO)-NICOTINIC ACID.
DR iPTMnet; Q9HBL8; -.
DR PhosphoSitePlus; Q9HBL8; -.
DR BioMuta; NMRAL1; -.
DR DMDM; 74734255; -.
DR CPTAC; CPTAC-1624; -.
DR EPD; Q9HBL8; -.
DR jPOST; Q9HBL8; -.
DR MassIVE; Q9HBL8; -.
DR MaxQB; Q9HBL8; -.
DR PaxDb; Q9HBL8; -.
DR PeptideAtlas; Q9HBL8; -.
DR PRIDE; Q9HBL8; -.
DR ProteomicsDB; 81572; -.
DR Antibodypedia; 24328; 108 antibodies from 25 providers.
DR DNASU; 57407; -.
DR Ensembl; ENST00000283429.11; ENSP00000283429.6; ENSG00000153406.14.
DR Ensembl; ENST00000404295.7; ENSP00000383962.3; ENSG00000153406.14.
DR Ensembl; ENST00000574425.5; ENSP00000460263.1; ENSG00000153406.14.
DR Ensembl; ENST00000574733.5; ENSP00000458762.1; ENSG00000153406.14.
DR Ensembl; ENST00000616587.2; ENSP00000479569.1; ENSG00000274684.4.
DR Ensembl; ENST00000621810.4; ENSP00000478990.1; ENSG00000274684.4.
DR Ensembl; ENST00000632013.1; ENSP00000488692.1; ENSG00000274684.4.
DR Ensembl; ENST00000633085.1; ENSP00000488644.1; ENSG00000274684.4.
DR GeneID; 57407; -.
DR KEGG; hsa:57407; -.
DR MANE-Select; ENST00000283429.11; ENSP00000283429.6; NM_020677.6; NP_065728.1.
DR UCSC; uc002cwm.4; human.
DR CTD; 57407; -.
DR DisGeNET; 57407; -.
DR GeneCards; NMRAL1; -.
DR HGNC; HGNC:24987; NMRAL1.
DR HPA; ENSG00000153406; Low tissue specificity.
DR neXtProt; NX_Q9HBL8; -.
DR OpenTargets; ENSG00000153406; -.
DR PharmGKB; PA145007922; -.
DR VEuPathDB; HostDB:ENSG00000153406; -.
DR eggNOG; ENOG502RG69; Eukaryota.
DR GeneTree; ENSGT00940000160872; -.
DR InParanoid; Q9HBL8; -.
DR OMA; TPMDGMA; -.
DR OrthoDB; 707551at2759; -.
DR PhylomeDB; Q9HBL8; -.
DR TreeFam; TF335532; -.
DR BioCyc; MetaCyc:ENSG00000153406-MON; -.
DR PathwayCommons; Q9HBL8; -.
DR Reactome; R-HSA-70635; Urea cycle.
DR SignaLink; Q9HBL8; -.
DR BioGRID-ORCS; 57407; 17 hits in 1028 CRISPR screens.
DR ChiTaRS; NMRAL1; human.
DR EvolutionaryTrace; Q9HBL8; -.
DR GenomeRNAi; 57407; -.
DR Pharos; Q9HBL8; Tbio.
DR PRO; PR:Q9HBL8; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; Q9HBL8; protein.
DR Bgee; ENSG00000153406; Expressed in granulocyte and 94 other tissues.
DR ExpressionAtlas; Q9HBL8; baseline and differential.
DR Genevisible; Q9HBL8; HS.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR008030; NmrA-like.
DR Pfam; PF05368; NmrA; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; NADP; Nucleus; Reference proteome.
FT CHAIN 1..299
FT /note="NmrA-like family domain-containing protein 1"
FT /id="PRO_0000278204"
FT REGION 153..189
FT /note="Interaction with ASS1"
FT BINDING 11..16
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:17496144"
FT BINDING 37..41
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:17496144"
FT BINDING 58..59
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:17496144"
FT BINDING 62
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /ligand_note="ligand shared between dimeric partners"
FT /evidence="ECO:0000269|PubMed:17496144"
FT BINDING 79..81
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:17496144"
FT BINDING 92
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /ligand_note="ligand shared between dimeric partners"
FT /evidence="ECO:0000269|PubMed:17496144"
FT BINDING 133
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:17496144"
FT BINDING 155..158
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /ligand_note="ligand shared between dimeric partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:17496144"
FT VARIANT 23
FT /note="T -> I (in dbSNP:rs11557236)"
FT /id="VAR_030689"
FT VARIANT 252
FT /note="P -> L (in dbSNP:rs3747582)"
FT /id="VAR_030690"
FT MUTAGEN 37
FT /note="R->A: Impairs binding to NADPH; abolishes the
FT ability to dimerize; enhances binding to ASS1; reduces
FT perinuclear localization."
FT /evidence="ECO:0000269|PubMed:19254724"
FT MUTAGEN 41
FT /note="K->S: Does not impair binding to NADPH; maintains
FT the dimerization properties as the wild type; does not
FT affect binding to ASS1; does not affect perinuclear
FT localization."
FT /evidence="ECO:0000269|PubMed:19254724"
FT MUTAGEN 81
FT /note="Y->A: Impairs binding to NADPH; abolishes the
FT ability to dimerize; enhances binding to ASS1; reduces
FT perinuclear localization."
FT /evidence="ECO:0000269|PubMed:19254724"
FT MUTAGEN 133
FT /note="K->A: Impairs binding to NADPH; enhances binding to
FT ASS1; reduces perinuclear localization."
FT /evidence="ECO:0000269|PubMed:19254724"
FT STRAND 6..10
FT /evidence="ECO:0007829|PDB:2WM3"
FT TURN 11..13
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 15..27
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 29..37
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 42..49
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 53..56
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 62..69
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 73..77
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 81..83
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 87..104
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 107..111
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 117..120
FT /evidence="ECO:0007829|PDB:2WM3"
FT TURN 121..123
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 128..143
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 147..151
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 156..160
FT /evidence="ECO:0007829|PDB:2WM3"
FT TURN 161..163
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 171..176
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 185..188
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 190..192
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 193..202
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 204..207
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 211..213
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 216..219
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 221..232
FT /evidence="ECO:0007829|PDB:2WM3"
FT STRAND 236..238
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 244..247
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 254..264
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 272..278
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 285..292
FT /evidence="ECO:0007829|PDB:2WM3"
FT HELIX 293..295
FT /evidence="ECO:0007829|PDB:2WM3"
SQ SEQUENCE 299 AA; 33344 MW; D740334F8F8D4E1E CRC64;
MVDKKLVVVF GGTGAQGGSV ARTLLEDGTF KVRVVTRNPR KKAAKELRLQ GAEVVQGDQD
DQVIMELALN GAYATFIVTN YWESCSQEQE VKQGKLLADL ARRLGLHYVV YSGLENIKKL
TAGRLAAAHF DGKGEVEEYF RDIGVPMTSV RLPCYFENLL SHFLPQKAPD GKSYLLSLPT
GDVPMDGMSV SDLGPVVLSL LKMPEKYVGQ NIGLSTCRHT AEEYAALLTK HTRKVVHDAK
MTPEDYEKLG FPGARDLANM FRFYALRPDR DIELTLRLNP KALTLDQWLE QHKGDFNLL
