NSDHL_MOUSE
ID NSDHL_MOUSE Reviewed; 362 AA.
AC Q9R1J0; O55109;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 153.
DE RecName: Full=Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating;
DE EC=1.1.1.170 {ECO:0000269|PubMed:10369263, ECO:0000269|PubMed:14567972};
GN Name=Nsdhl;
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 [MRNA], CATALYTIC ACTIVITY, FUNCTION, VARIANTS STR
RP LEU-98 AND MET-109, AND VARIANT BPA 103-LYS--LYS-362 DEL.
RX PubMed=10369263; DOI=10.1038/9700;
RA Liu X.Y., Dangel A.W., Kelley R.I., Zhao W., Denny P., Botcherby M.,
RA Cattanach B., Peters J., Hunsicker P.R., Mallon A.-M., Strivens M.A.,
RA Bate R., Miller W., Rhodes M., Brown S.D.M., Herman G.E.;
RT "The gene mutated in bare patches and striated mice encodes a novel 3beta-
RT hydroxysteroid dehydrogenase.";
RL Nat. Genet. 22:182-187(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=10854409; DOI=10.1101/gr.10.6.758;
RA Mallon A.-M., Platzer M., Bate R., Gloeckner G., Botcherby M.R.M.,
RA Nordsiek G., Strivens M.A., Kioschis P., Dangel A., Cunningham D.,
RA Straw R.N.A., Weston P., Gilbert M., Fernando S., Goodall K., Hunter G.,
RA Greystrong J.S., Clarke D., Kimberley C., Goerdes M., Blechschmidt K.,
RA Rump A., Hinzmann B., Mundy C.R., Miller W., Poustka A., Herman G.E.,
RA Rhodes M., Denny P., Rosenthal A., Brown S.D.M.;
RT "Comparative genome sequence analysis of the Bpa/Str region in mouse and
RT man.";
RL Genome Res. 10:758-775(2000).
RN [3]
RP SUBCELLULAR LOCATION, AND ER RETENTION MOTIF.
RX PubMed=14506130; DOI=10.1093/hmg/ddg321;
RA Caldas H., Herman G.E.;
RT "NSDHL, an enzyme involved in cholesterol biosynthesis, traffics through
RT the Golgi and accumulates on ER membranes and on the surface of lipid
RT droplets.";
RL Hum. Mol. Genet. 12:2981-2991(2003).
RN [4]
RP CATALYTIC ACTIVITY, FUNCTION, VARIANTS BPA ASP-53 AND THR-94,
RP CHARACTERIZATION OF VARIANTS BPA ASP-53 AND THR-94, AND CHARACTERIZATION OF
RP VARIANTS STR LEU-98 AND MET-109.
RX PubMed=14567972; DOI=10.1016/s1096-7192(03)00137-9;
RA Lucas M.E., Ma Q., Cunningham D., Peters J., Cattanach B., Bard M.,
RA Elmore B.K., Herman G.E.;
RT "Identification of two novel mutations in the murine Nsdhl sterol
RT dehydrogenase gene and development of a functional complementation assay in
RT yeast.";
RL Mol. Genet. Metab. 80:227-233(2003).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Kidney, Liver, Lung, Pancreas, Spleen,
RC and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP FUNCTION.
RX PubMed=23125191; DOI=10.1158/2159-8290.cd-12-0031;
RA Sukhanova A., Gorin A., Serebriiskii I.G., Gabitova L., Zheng H.,
RA Restifo D., Egleston B.L., Cunningham D., Bagnyukova T., Liu H.,
RA Nikonova A., Adams G.P., Zhou Y., Yang D.H., Mehra R., Burtness B.,
RA Cai K.Q., Klein-Szanto A., Kratz L.E., Kelley R.I., Weiner L.M.,
RA Herman G.E., Golemis E.A., Astsaturov I.;
RT "Targeting C4-demethylating genes in the cholesterol pathway sensitizes
RT cancer cells to EGF receptor inhibitors via increased EGF receptor
RT degradation.";
RL Cancer Discov. 3:96-111(2013).
CC -!- FUNCTION: Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation
CC of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene
CC cholesterol biosynthesis (PubMed:10369263, PubMed:14567972). Plays a
CC role in the regulation of the endocytic trafficking of EGFR
CC (PubMed:23125191). {ECO:0000269|PubMed:10369263,
CC ECO:0000269|PubMed:14567972, ECO:0000269|PubMed:23125191}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 3beta-hydroxysteroid-4alpha-carboxylate + NADP(+) = a 3-
CC oxosteroid + CO2 + NADPH; Xref=Rhea:RHEA:34771, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:47788, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:136966; EC=1.1.1.170;
CC Evidence={ECO:0000269|PubMed:10369263, ECO:0000269|PubMed:14567972};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(+) = a 3-
CC oxosteroid + CO2 + NADH; Xref=Rhea:RHEA:34775, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:47788, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC ChEBI:CHEBI:136966; EC=1.1.1.170;
CC Evidence={ECO:0000269|PubMed:10369263, ECO:0000269|PubMed:14567972};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4alpha-carboxyzymosterol + NADP(+) = CO2 + NADPH +
CC zymosterone; Xref=Rhea:RHEA:33455, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:52386, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:143575; Evidence={ECO:0000269|PubMed:10369263,
CC ECO:0000269|PubMed:14567972};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33456;
CC Evidence={ECO:0000305|PubMed:10369263, ECO:0000305|PubMed:14567972};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4alpha-carboxy-4beta-methyl-5alpha-cholest-8-en-3beta-ol +
CC NADP(+) = 4alpha-methyl-5alpha-cholest-8-en-3-one + CO2 + NADPH;
CC Xref=Rhea:RHEA:46828, ChEBI:CHEBI:16526, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:87047, ChEBI:CHEBI:87050;
CC Evidence={ECO:0000269|PubMed:10369263, ECO:0000269|PubMed:14567972};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46829;
CC Evidence={ECO:0000305|PubMed:10369263, ECO:0000305|PubMed:14567972};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4alpha-carboxy-5alpha-cholest-8-ene-3beta-ol + NADP(+) =
CC 5alpha-cholest-8-en-3-one + CO2 + NADPH; Xref=Rhea:RHEA:46848,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:87055, ChEBI:CHEBI:87056;
CC Evidence={ECO:0000269|PubMed:10369263, ECO:0000269|PubMed:14567972};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46849;
CC Evidence={ECO:0000305|PubMed:10369263, ECO:0000305|PubMed:14567972};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4beta-methylzymosterol-4alpha-carboxylate + NADP(+) = 3-
CC dehydro-4-methylzymosterol + CO2 + NADPH; Xref=Rhea:RHEA:33447,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:50593, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:64925; EC=1.1.1.170;
CC Evidence={ECO:0000269|PubMed:14567972};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33448;
CC Evidence={ECO:0000305|PubMed:14567972};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4beta-methylzymosterol-4alpha-carboxylate + NAD(+) = 3-
CC dehydro-4-methylzymosterol + CO2 + NADH; Xref=Rhea:RHEA:47160,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:50593, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:64925;
CC Evidence={ECO:0000269|PubMed:14567972};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47161;
CC Evidence={ECO:0000305|PubMed:14567972};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4alpha-carboxy-5alpha-cholest-8-ene-3beta-ol + NAD(+) =
CC 5alpha-cholest-8-en-3-one + CO2 + NADH; Xref=Rhea:RHEA:47172,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945,
CC ChEBI:CHEBI:87055, ChEBI:CHEBI:87056;
CC Evidence={ECO:0000269|PubMed:14567972};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47173;
CC Evidence={ECO:0000305|PubMed:14567972};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4alpha-carboxy-4beta-methyl-5alpha-cholest-8-en-3beta-ol +
CC NAD(+) = 4alpha-methyl-5alpha-cholest-8-en-3-one + CO2 + NADH;
CC Xref=Rhea:RHEA:47168, ChEBI:CHEBI:16526, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:87047, ChEBI:CHEBI:87050;
CC Evidence={ECO:0000269|PubMed:14567972};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47169;
CC Evidence={ECO:0000305|PubMed:14567972};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4alpha-carboxyzymosterol + NAD(+) = CO2 + NADH + zymosterone;
CC Xref=Rhea:RHEA:47164, ChEBI:CHEBI:16526, ChEBI:CHEBI:52386,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:143575;
CC Evidence={ECO:0000269|PubMed:14567972};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47165;
CC Evidence={ECO:0000305|PubMed:14567972};
CC -!- PATHWAY: Steroid biosynthesis; zymosterol biosynthesis; zymosterol from
CC lanosterol: step 4/6.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:Q15738}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:14506130}; Single-pass membrane protein
CC {ECO:0000255}. Lipid droplet {ECO:0000269|PubMed:14506130}.
CC Note=Trafficking through the Golgi is necessary for ER membrane
CC localization. {ECO:0000269|PubMed:14506130}.
CC -!- DISEASE: Note=Defects in Nsdhl are the cause of male-lethal mutations
CC bare patches (Bpa) and striated (Str) phenotypes. Heterozygous Bpa
CC females are dwarfed and demonstrate abnormal deposits of calcium in
CC tail vertebrae. They also develop a hyperkeratotic skin eruption
CC shortly after birth that resolves, leaving 'bare patches' arranged in a
CC horizontal, striped pattern. The Str females are indistinguishable from
CC normal littermates until postnatal day 12-14 when they develop
CC striations in their coat. {ECO:0000269|PubMed:10369263,
CC ECO:0000269|PubMed:14567972}.
CC -!- SIMILARITY: Belongs to the 3-beta-HSD family. {ECO:0000305}.
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DR EMBL; AF100198; AAD38448.1; -; mRNA.
DR EMBL; AL021127; CAA15948.2; -; Genomic_DNA.
DR CCDS; CCDS30190.1; -.
DR RefSeq; NP_035071.3; NM_010941.3.
DR AlphaFoldDB; Q9R1J0; -.
DR SMR; Q9R1J0; -.
DR BioGRID; 201856; 5.
DR STRING; 10090.ENSMUSP00000033715; -.
DR SwissLipids; SLP:000001303; -.
DR iPTMnet; Q9R1J0; -.
DR PhosphoSitePlus; Q9R1J0; -.
DR SwissPalm; Q9R1J0; -.
DR EPD; Q9R1J0; -.
DR jPOST; Q9R1J0; -.
DR MaxQB; Q9R1J0; -.
DR PaxDb; Q9R1J0; -.
DR PRIDE; Q9R1J0; -.
DR ProteomicsDB; 253019; -.
DR Antibodypedia; 349; 143 antibodies from 24 providers.
DR DNASU; 18194; -.
DR Ensembl; ENSMUST00000033715; ENSMUSP00000033715; ENSMUSG00000031349.
DR GeneID; 18194; -.
DR KEGG; mmu:18194; -.
DR UCSC; uc009tkv.1; mouse.
DR CTD; 50814; -.
DR MGI; MGI:1099438; Nsdhl.
DR VEuPathDB; HostDB:ENSMUSG00000031349; -.
DR eggNOG; KOG1430; Eukaryota.
DR GeneTree; ENSGT00940000158229; -.
DR HOGENOM; CLU_007383_6_8_1; -.
DR InParanoid; Q9R1J0; -.
DR OMA; WGPGDTQ; -.
DR OrthoDB; 930591at2759; -.
DR PhylomeDB; Q9R1J0; -.
DR TreeFam; TF354279; -.
DR BRENDA; 1.1.1.170; 3474.
DR Reactome; R-MMU-191273; Cholesterol biosynthesis.
DR UniPathway; UPA00770; UER00757.
DR BioGRID-ORCS; 18194; 8 hits in 76 CRISPR screens.
DR ChiTaRS; Nsdhl; mouse.
DR PRO; PR:Q9R1J0; -.
DR Proteomes; UP000000589; Chromosome X.
DR RNAct; Q9R1J0; protein.
DR Bgee; ENSMUSG00000031349; Expressed in left lobe of liver and 255 other tissues.
DR ExpressionAtlas; Q9R1J0; baseline and differential.
DR Genevisible; Q9R1J0; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005811; C:lipid droplet; IDA:UniProtKB.
DR GO; GO:0003854; F:3-beta-hydroxy-delta5-steroid dehydrogenase activity; IEA:InterPro.
DR GO; GO:0102175; F:3-beta-hydroxysteroid dehydrogenase/C4-decarboxylase activity; IEA:RHEA.
DR GO; GO:0103066; F:4alpha-carboxy-4beta-methyl-5alpha-cholesta-8-en-3beta-ol:NAD(P)+ 3-oxidoreductase (decarboxylating) activity; IEA:UniProtKB-EC.
DR GO; GO:0103067; F:4alpha-carboxy-5alpha-cholesta-8-en-3beta-ol:NAD(P)+ 3-dehydrogenase (decarboxylating) activity; IEA:UniProtKB-EC.
DR GO; GO:0000252; F:C-3 sterol dehydrogenase (C-4 sterol decarboxylase) activity; IEA:UniProtKB-EC.
DR GO; GO:0016616; F:oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor; IBA:GO_Central.
DR GO; GO:0047012; F:sterol-4-alpha-carboxylate 3-dehydrogenase (decarboxylating) activity; IEA:UniProtKB-EC.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0008203; P:cholesterol metabolic process; IMP:MGI.
DR GO; GO:0001942; P:hair follicle development; IMP:MGI.
DR GO; GO:0060716; P:labyrinthine layer blood vessel development; IMP:MGI.
DR GO; GO:0007224; P:smoothened signaling pathway; IGI:MGI.
DR InterPro; IPR002225; 3Beta_OHSteriod_DH/Estase.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR Pfam; PF01073; 3Beta_HSD; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cholesterol biosynthesis; Cholesterol metabolism;
KW Disease variant; Endoplasmic reticulum; Lipid biosynthesis; Lipid droplet;
KW Lipid metabolism; Membrane; NAD; Oxidoreductase; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transmembrane; Transmembrane helix.
FT CHAIN 1..362
FT /note="Sterol-4-alpha-carboxylate 3-dehydrogenase,
FT decarboxylating"
FT /id="PRO_0000087800"
FT TRANSMEM 287..307
FT /note="Helical"
FT /evidence="ECO:0000255"
FT MOTIF 359..362
FT /note="Prevents secretion from ER"
FT /evidence="ECO:0000269|PubMed:14506130"
FT ACT_SITE 161
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q12068"
FT BINDING 165
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q12068"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0000250|UniProtKB:Q15738"
FT VARIANT 53
FT /note="V -> D (in bpa; does not rescue the yeast mutant
FT lacking the ortholog erg26)"
FT /evidence="ECO:0000269|PubMed:14567972"
FT VARIANT 94
FT /note="A -> T (in bpa; does not rescue the yeast mutant
FT lacking the ortholog erg26)"
FT /evidence="ECO:0000269|PubMed:14567972"
FT VARIANT 98
FT /note="P -> L (in str; does not rescue the yeast mutant
FT lacking the ortholog erg26)"
FT /evidence="ECO:0000269|PubMed:10369263"
FT VARIANT 103..362
FT /note="Missing (in bpa)"
FT /evidence="ECO:0000269|PubMed:10369263"
FT VARIANT 109
FT /note="V -> M (in str; rescues the yeast mutant lacking the
FT ortholog erg26)"
FT /evidence="ECO:0000269|PubMed:10369263"
SQ SEQUENCE 362 AA; 40686 MW; 4DB53EC0314885C3 CRC64;
MEQAVHGESK RGQVTGTHLT NDISKAKKCT VIGGSGFLGQ HMVEQLLERG YTVNVFDIHQ
GFDNPRVQFF IGDLCNQQDL YPALKGVSTV FHCASPPPYS NNKELFYRVN FIGTKTVIET
CREAGVQKLI LTSSASVVFE GVDIKNGTED LPYAMKPIDY YTETKILQER AVLDANDPKK
NFLTAAIRPH GIFGPRDPQL VPILIDAARK GKMKFMIGNG ENLVDFTFVE NVVHGHILAA
EHLSQDAALG GKAFHITNDE PIPFWTFLSR ILTGLNYEAP KYHIPYWMAY YLAFLLSLLV
MVVSPLIQIQ PTFTPIRVAL AGTFHYYSCE KAKKLFGYRP LVTMDEAVER TVQSFHHLRK
DK
