DHDDS_HUMAN
ID DHDDS_HUMAN Reviewed; 333 AA.
AC Q86SQ9; B7Z4B9; B7ZB20; D3DPK7; D3DPK8; D3DPK9; E9KL43; Q5T0A4; Q8NE90;
AC Q9BTG5; Q9BTK3; Q9H905;
DT 13-APR-2004, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 3.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Dehydrodolichyl diphosphate synthase complex subunit DHDDS {ECO:0000305};
DE EC=2.5.1.87 {ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:28842490};
DE AltName: Full=Cis-isoprenyltransferase {ECO:0000303|PubMed:14652022};
DE Short=CIT {ECO:0000303|PubMed:28842490};
DE Short=Cis-IPTase {ECO:0000303|PubMed:14652022};
DE AltName: Full=Cis-prenyltransferase subunit hCIT {ECO:0000303|PubMed:28842490};
DE AltName: Full=Epididymis tissue protein Li 189m;
GN Name=DHDDS {ECO:0000303|PubMed:21295283, ECO:0000312|HGNC:HGNC:20603};
GN Synonyms=HDS;
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 [MRNA] (ISOFORM 1).
RC TISSUE=Testis;
RX PubMed=12591616; DOI=10.1016/s0167-4781(02)00628-0;
RA Endo S., Zhang Y.-W., Takahashi S., Koyama T.;
RT "Identification of human dehydrodolichyl diphosphate synthase gene.";
RL Biochim. Biophys. Acta 1625:291-295(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT MET-253, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Epididymis;
RX PubMed=20736409; DOI=10.1074/mcp.m110.001719;
RA Li J., Liu F., Wang H., Liu X., Liu J., Li N., Wan F., Wang W., Zhang C.,
RA Jin S., Liu J., Zhu P., Liu Y.;
RT "Systematic mapping and functional analysis of a family of human epididymal
RT secretory sperm-located proteins.";
RL Mol. Cell. Proteomics 9:2517-2528(2010).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 4), AND VARIANT
RP MET-253.
RC TISSUE=Teratocarcinoma, and Thyroid;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3), AND VARIANT
RP MET-253.
RC TISSUE=Lung, Muscle, and Placenta;
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 [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=14652022; DOI=10.1016/j.bbrc.2003.11.065;
RA Shridas P., Rush J.S., Waechter C.J.;
RT "Identification and characterization of a cDNA encoding a long-chain cis-
RT isoprenyltransferase involved in dolichyl monophosphate biosynthesis in the
RT ER of brain cells.";
RL Biochem. Biophys. Res. Commun. 312:1349-1356(2003).
RN [8]
RP INTERACTION WITH NUS1.
RX PubMed=21572394; DOI=10.1038/emboj.2011.147;
RA Harrison K.D., Park E.J., Gao N., Kuo A., Rush J.S., Waechter C.J.,
RA Lehrman M.A., Sessa W.C.;
RT "Nogo-B receptor is necessary for cellular dolichol biosynthesis and
RT protein N-glycosylation.";
RL EMBO J. 30:2490-2500(2011).
RN [9]
RP CATALYTIC ACTIVITY, FUNCTION, SUBUNIT, AND PATHWAY.
RX PubMed=25066056; DOI=10.1016/j.cmet.2014.06.016;
RA Park E.J., Grabinska K.A., Guan Z., Stranecky V., Hartmannova H.,
RA Hodanova K., Baresova V., Sovova J., Jozsef L., Ondruskova N.,
RA Hansikova H., Honzik T., Zeman J., Hulkova H., Wen R., Kmoch S.,
RA Sessa W.C.;
RT "Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a
RT congenital disorder of glycosylation.";
RL Cell Metab. 20:448-457(2014).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [11]
RP COFACTOR, SUBUNIT, CATALYTIC ACTIVITY, FUNCTION, CHARACTERIZATION OF
RP VARIANT GLU-42, BIOPHYSICOCHEMICAL PROPERTIES, PATHWAY, AND ACTIVITY
RP REGULATION.
RX PubMed=28842490; DOI=10.1074/jbc.m117.806034;
RA Grabinska K.A., Edani B.H., Park E.J., Kraehling J.R., Sessa W.C.;
RT "A conserved C-terminal RXG motif in the NgBR subunit of cis-
RT prenyltransferase is critical for prenyltransferase activity.";
RL J. Biol. Chem. 292:17351-17361(2017).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.31 ANGSTROMS) OF 1-333 IN COMPLEX WITH NUS1;
RP ISOPENTENYL DIPHOSPHATE AND MAGNESIUM, FUNCTION, CATALYTIC ACTIVITY,
RP COFACTOR, ACTIVITY REGULATION, DOMAIN, AND MUTAGENESIS OF TRP-12; PHE-15;
RP ILE-19; 106-GLU--GLU-109; ARG-306; PHE-313 AND LEU-317.
RX PubMed=32817466; DOI=10.1073/pnas.2008381117;
RA Edani B.H., Grabinska K.A., Zhang R., Park E.J., Siciliano B., Surmacz L.,
RA Ha Y., Sessa W.C.;
RT "Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex
RT reveals insights in regulation of protein glycosylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 117:20794-20802(2020).
RN [13]
RP VARIANT RP59 GLU-42.
RX PubMed=21295283; DOI=10.1016/j.ajhg.2011.01.001;
RA Zuchner S., Dallman J., Wen R., Beecham G., Naj A., Farooq A., Kohli M.A.,
RA Whitehead P.L., Hulme W., Konidari I., Edwards Y.J., Cai G., Peter I.,
RA Seo D., Buxbaum J.D., Haines J.L., Blanton S., Young J., Alfonso E.,
RA Vance J.M., Lam B.L., Pericak-Vance M.A.;
RT "Whole-exome sequencing links a variant in DHDDS to retinitis pigmentosa.";
RL Am. J. Hum. Genet. 88:201-206(2011).
RN [14]
RP INVOLVEMENT IN DEDSM, AND VARIANTS DEDSM HIS-37 AND GLN-211.
RX PubMed=29100083; DOI=10.1016/j.ajhg.2017.09.008;
RG Deciphering Developmental Disorders Study;
RA Hamdan F.F., Myers C.T., Cossette P., Lemay P., Spiegelman D.,
RA Laporte A.D., Nassif C., Diallo O., Monlong J., Cadieux-Dion M.,
RA Dobrzeniecka S., Meloche C., Retterer K., Cho M.T., Rosenfeld J.A., Bi W.,
RA Massicotte C., Miguet M., Brunga L., Regan B.M., Mo K., Tam C.,
RA Schneider A., Hollingsworth G., FitzPatrick D.R., Donaldson A., Canham N.,
RA Blair E., Kerr B., Fry A.E., Thomas R.H., Shelagh J., Hurst J.A.,
RA Brittain H., Blyth M., Lebel R.R., Gerkes E.H., Davis-Keppen L., Stein Q.,
RA Chung W.K., Dorison S.J., Benke P.J., Fassi E., Corsten-Janssen N.,
RA Kamsteeg E.J., Mau-Them F.T., Bruel A.L., Verloes A., Ounap K.,
RA Wojcik M.H., Albert D.V.F., Venkateswaran S., Ware T., Jones D., Liu Y.C.,
RA Mohammad S.S., Bizargity P., Bacino C.A., Leuzzi V., Martinelli S.,
RA Dallapiccola B., Tartaglia M., Blumkin L., Wierenga K.J., Purcarin G.,
RA O'Byrne J.J., Stockler S., Lehman A., Keren B., Nougues M.C., Mignot C.,
RA Auvin S., Nava C., Hiatt S.M., Bebin M., Shao Y., Scaglia F., Lalani S.R.,
RA Frye R.E., Jarjour I.T., Jacques S., Boucher R.M., Riou E., Srour M.,
RA Carmant L., Lortie A., Major P., Diadori P., Dubeau F., D'Anjou G.,
RA Bourque G., Berkovic S.F., Sadleir L.G., Campeau P.M., Kibar Z.,
RA Lafreniere R.G., Girard S.L., Mercimek-Mahmutoglu S., Boelman C.,
RA Rouleau G.A., Scheffer I.E., Mefford H.C., Andrade D.M., Rossignol E.,
RA Minassian B.A., Michaud J.L.;
RT "High rate of recurrent de novo mutations in developmental and epileptic
RT encephalopathies.";
RL Am. J. Hum. Genet. 101:664-685(2017).
RN [15]
RP VARIANTS ASN-95; GLN-205 AND GLN-211.
RX PubMed=33798445; DOI=10.1016/j.ajhg.2021.03.013;
RA Courage C., Oliver K.L., Park E.J., Cameron J.M., Grabinska K.A., Muona M.,
RA Canafoglia L., Gambardella A., Said E., Afawi Z., Baykan B., Brandt C.,
RA di Bonaventura C., Chew H.B., Criscuolo C., Dibbens L.M., Castellotti B.,
RA Riguzzi P., Labate A., Filla A., Giallonardo A.T., Berecki G.,
RA Jackson C.B., Joensuu T., Damiano J.A., Kivity S., Korczyn A., Palotie A.,
RA Striano P., Uccellini D., Giuliano L., Andermann E., Scheffer I.E.,
RA Michelucci R., Bahlo M., Franceschetti S., Sessa W.C., Berkovic S.F.,
RA Lehesjoki A.E.;
RT "Progressive myoclonus epilepsies-Residual unsolved cases have marked
RT genetic heterogeneity including dolichol-dependent protein glycosylation
RT pathway genes.";
RL Am. J. Hum. Genet. 108:722-738(2021).
CC -!- FUNCTION: With NUS1, forms the dehydrodolichyl diphosphate synthase
CC (DDS) complex, an essential component of the dolichol monophosphate
CC (Dol-P) biosynthetic machinery. Both subunits contribute to enzymatic
CC activity, i.e. condensation of multiple copies of isopentenyl
CC pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) to produce
CC dehydrodolichyl diphosphate (Dedol-PP), a precursor of dolichol
CC phosphate which is utilized as a sugar carrier in protein glycosylation
CC in the endoplasmic reticulum (ER) (PubMed:25066056, PubMed:28842490,
CC PubMed:32817466). Synthesizes long-chain polyprenols, mostly of C95 and
CC C100 chain length (PubMed:32817466). Regulates the glycosylation and
CC stability of nascent NPC2, thereby promoting trafficking of LDL-derived
CC cholesterol (PubMed:21572394). {ECO:0000269|PubMed:21572394,
CC ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:28842490,
CC ECO:0000269|PubMed:32817466}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2E,6E)-farnesyl diphosphate + n isopentenyl diphosphate = di-
CC trans,poly-cis-polyprenyl diphosphate + n diphosphate;
CC Xref=Rhea:RHEA:53008, Rhea:RHEA-COMP:13431, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:128769, ChEBI:CHEBI:136960, ChEBI:CHEBI:175763;
CC EC=2.5.1.87; Evidence={ECO:0000269|PubMed:25066056,
CC ECO:0000269|PubMed:28842490, ECO:0000269|PubMed:32817466};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:28842490, ECO:0000269|PubMed:32817466};
CC Note=Binds 1 magnesium ion per subunit. {ECO:0000269|PubMed:32817466};
CC -!- ACTIVITY REGULATION: Activated by phospholipids including cardiolipin,
CC phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol and
CC phosphatidylserine. {ECO:0000269|PubMed:28842490}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=11.1 uM for isopentenyl diphosphate {ECO:0000269|PubMed:28842490};
CC KM=0.68 uM for (2E,6E)-farnesyl diphosphate
CC {ECO:0000269|PubMed:28842490};
CC Note=Values were measured with the heterodimer. kcat is 0.58 sec(-1)
CC with (2E,6E)-farnesyl diphosphate and isopentenyl diphosphate as
CC substrate. {ECO:0000269|PubMed:28842490};
CC pH dependence:
CC Optimum pH is 8-9. Active from pH 5.5 to 9.3.
CC {ECO:0000269|PubMed:28842490};
CC -!- PATHWAY: Protein modification; protein glycosylation.
CC {ECO:0000269|PubMed:25066056}.
CC -!- PATHWAY: Lipid metabolism. {ECO:0000269|PubMed:28842490}.
CC -!- SUBUNIT: Forms an active dehydrodolichyl diphosphate synthase complex
CC with NUS1 (PubMed:25066056, PubMed:28842490, PubMed:32817466).
CC Interacts with NPC2 (PubMed:21572394). {ECO:0000269|PubMed:21572394,
CC ECO:0000269|PubMed:25066056, ECO:0000269|PubMed:28842490}.
CC -!- INTERACTION:
CC Q86SQ9; Q96E22: NUS1; NbExp=3; IntAct=EBI-26942900, EBI-6949352;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:14652022}; Peripheral membrane protein
CC {ECO:0000269|PubMed:14652022}. Note=colocalizes with calnexin.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q86SQ9-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q86SQ9-2; Sequence=VSP_010031;
CC Name=3;
CC IsoId=Q86SQ9-3; Sequence=VSP_010030;
CC Name=4;
CC IsoId=Q86SQ9-4; Sequence=VSP_045007;
CC -!- TISSUE SPECIFICITY: Expressed at high levels in testis and kidney.
CC Expressed in epididymis (at protein level). Slightly expressed in
CC heart, spleen and thymus. {ECO:0000269|PubMed:20736409}.
CC -!- DOMAIN: The catalytic site at NUS1-DHDDS interface accomodates both the
CC allylic and the homoallylic IPP substrates to the S1 and S2 pockets
CC respectively. The beta-phosphate groups of IPP substrates form hydrogen
CC bonds with the RXG motif of NUS1 and four conserved residues of DHDDS
CC (Arg-85, Arg-205, Arg-211 and Ser-213), while the allylic isopentenyl
CC group is pointed toward the hydrophobic tunnel of the S1 pocket where
CC the product elongation occurs. {ECO:0000269|PubMed:32817466}.
CC -!- DISEASE: Retinitis pigmentosa 59 (RP59) [MIM:613861]: A retinal
CC dystrophy belonging to the group of pigmentary retinopathies. Retinitis
CC pigmentosa is characterized by retinal pigment deposits visible on
CC fundus examination and primary loss of rod photoreceptor cells followed
CC by secondary loss of cone photoreceptors. Patients typically have night
CC vision blindness and loss of midperipheral visual field. As their
CC condition progresses, they lose their far peripheral visual field and
CC eventually central vision as well. {ECO:0000269|PubMed:21295283}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- DISEASE: Developmental delay and seizures with or without movement
CC abnormalities (DEDSM) [MIM:617836]: An autosomal dominant
CC neurodevelopmental disorder characterized by global developmental
CC delay, variable intellectual disability, and early-onset seizures with
CC a myoclonic component. Most patients have delayed motor development and
CC show abnormal movements, including ataxia, dystonia, and tremor.
CC {ECO:0000269|PubMed:29100083}. Note=The disease may be caused by
CC variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: [Isoform 3]: May be due to exon skipping. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the UPP synthase family. {ECO:0000305}.
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DR EMBL; AB090852; BAC57588.1; -; mRNA.
DR EMBL; GU727641; ADU87642.1; -; mRNA.
DR EMBL; AK023164; BAB14439.1; -; mRNA.
DR EMBL; AK297134; BAH12505.1; -; mRNA.
DR EMBL; AK316485; BAH14856.1; -; mRNA.
DR EMBL; AL513365; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471059; EAX07806.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07808.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07809.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07810.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07811.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX07812.1; -; Genomic_DNA.
DR EMBL; BC003643; AAH03643.1; -; mRNA.
DR EMBL; BC004117; AAH04117.1; -; mRNA.
DR EMBL; BC034152; AAH34152.1; -; mRNA.
DR CCDS; CCDS281.1; -. [Q86SQ9-2]
DR CCDS; CCDS282.1; -. [Q86SQ9-1]
DR CCDS; CCDS57983.1; -. [Q86SQ9-4]
DR CCDS; CCDS57984.1; -. [Q86SQ9-3]
DR RefSeq; NP_001230493.1; NM_001243564.1. [Q86SQ9-4]
DR RefSeq; NP_001230494.1; NM_001243565.1. [Q86SQ9-3]
DR RefSeq; NP_079163.2; NM_024887.3. [Q86SQ9-2]
DR RefSeq; NP_995583.1; NM_205861.2. [Q86SQ9-1]
DR RefSeq; XP_006710975.1; XM_006710912.2.
DR RefSeq; XP_006710976.1; XM_006710913.2.
DR RefSeq; XP_006710977.1; XM_006710914.2.
DR RefSeq; XP_011540485.1; XM_011542183.2.
DR RefSeq; XP_011540486.1; XM_011542184.2.
DR RefSeq; XP_011540488.1; XM_011542186.2.
DR RefSeq; XP_016857868.1; XM_017002379.1.
DR RefSeq; XP_016857869.1; XM_017002380.1.
DR PDB; 6W2L; X-ray; 2.31 A; A=2-330.
DR PDB; 6Z1N; X-ray; 2.30 A; A=1-333.
DR PDBsum; 6W2L; -.
DR PDBsum; 6Z1N; -.
DR AlphaFoldDB; Q86SQ9; -.
DR SASBDB; Q86SQ9; -.
DR SMR; Q86SQ9; -.
DR BioGRID; 123018; 12.
DR ComplexPortal; CPX-6701; Dehydrodolichyl diphosphate synthase complex.
DR CORUM; Q86SQ9; -.
DR IntAct; Q86SQ9; 2.
DR STRING; 9606.ENSP00000353104; -.
DR iPTMnet; Q86SQ9; -.
DR PhosphoSitePlus; Q86SQ9; -.
DR BioMuta; DHDDS; -.
DR DMDM; 116241329; -.
DR EPD; Q86SQ9; -.
DR jPOST; Q86SQ9; -.
DR MassIVE; Q86SQ9; -.
DR MaxQB; Q86SQ9; -.
DR PaxDb; Q86SQ9; -.
DR PeptideAtlas; Q86SQ9; -.
DR PRIDE; Q86SQ9; -.
DR ProteomicsDB; 6588; -.
DR ProteomicsDB; 69620; -. [Q86SQ9-1]
DR ProteomicsDB; 69621; -. [Q86SQ9-2]
DR ProteomicsDB; 69622; -. [Q86SQ9-3]
DR Antibodypedia; 16091; 112 antibodies from 22 providers.
DR DNASU; 79947; -.
DR Ensembl; ENST00000236342.12; ENSP00000236342.7; ENSG00000117682.17. [Q86SQ9-1]
DR Ensembl; ENST00000360009.6; ENSP00000353104.2; ENSG00000117682.17. [Q86SQ9-2]
DR Ensembl; ENST00000525682.6; ENSP00000434984.1; ENSG00000117682.17. [Q86SQ9-4]
DR Ensembl; ENST00000526219.5; ENSP00000434219.1; ENSG00000117682.17. [Q86SQ9-3]
DR GeneID; 79947; -.
DR KEGG; hsa:79947; -.
DR MANE-Select; ENST00000236342.12; ENSP00000236342.7; NM_205861.3; NP_995583.1.
DR UCSC; uc001bmk.4; human. [Q86SQ9-1]
DR CTD; 79947; -.
DR DisGeNET; 79947; -.
DR GeneCards; DHDDS; -.
DR GeneReviews; DHDDS; -.
DR HGNC; HGNC:20603; DHDDS.
DR HPA; ENSG00000117682; Low tissue specificity.
DR MalaCards; DHDDS; -.
DR MIM; 608172; gene.
DR MIM; 613861; phenotype.
DR MIM; 617836; phenotype.
DR neXtProt; NX_Q86SQ9; -.
DR OpenTargets; ENSG00000117682; -.
DR Orphanet; 442835; Non-specific early-onset epileptic encephalopathy.
DR Orphanet; 791; Retinitis pigmentosa.
DR PharmGKB; PA134867119; -.
DR VEuPathDB; HostDB:ENSG00000117682; -.
DR eggNOG; KOG1602; Eukaryota.
DR GeneTree; ENSGT00390000007879; -.
DR InParanoid; Q86SQ9; -.
DR OMA; PRTEGHK; -.
DR OrthoDB; 1362420at2759; -.
DR PhylomeDB; Q86SQ9; -.
DR TreeFam; TF323753; -.
DR BioCyc; MetaCyc:HS04165-MON; -.
DR BRENDA; 2.5.1.87; 2681.
DR PathwayCommons; Q86SQ9; -.
DR Reactome; R-HSA-446199; Synthesis of Dolichyl-phosphate.
DR Reactome; R-HSA-4755609; Defective DHDDS causes RP59.
DR SignaLink; Q86SQ9; -.
DR UniPathway; UPA00378; -.
DR BioGRID-ORCS; 79947; 810 hits in 1078 CRISPR screens.
DR ChiTaRS; DHDDS; human.
DR GeneWiki; Dehydrodolichyl_diphosphate_synthase; -.
DR GeneWiki; DHDDS; -.
DR GenomeRNAi; 79947; -.
DR Pharos; Q86SQ9; Tbio.
DR PRO; PR:Q86SQ9; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q86SQ9; protein.
DR Bgee; ENSG00000117682; Expressed in sperm and 180 other tissues.
DR ExpressionAtlas; Q86SQ9; baseline and differential.
DR Genevisible; Q86SQ9; HS.
DR GO; GO:1904423; C:dehydrodolichyl diphosphate synthase complex; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0045547; F:dehydrodolichyl diphosphate synthase activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0006489; P:dolichyl diphosphate biosynthetic process; IDA:UniProtKB.
DR GO; GO:0016094; P:polyprenol biosynthetic process; IBA:GO_Central.
DR CDD; cd00475; Cis_IPPS; 1.
DR Gene3D; 3.40.1180.10; -; 1.
DR HAMAP; MF_01139; ISPT; 1.
DR InterPro; IPR001441; UPP_synth-like.
DR InterPro; IPR018520; UPP_synth-like_CS.
DR InterPro; IPR036424; UPP_synth-like_sf.
DR PANTHER; PTHR10291; PTHR10291; 1.
DR Pfam; PF01255; Prenyltransf; 1.
DR SUPFAM; SSF64005; SSF64005; 1.
DR TIGRFAMs; TIGR00055; uppS; 1.
DR PROSITE; PS01066; UPP_SYNTHASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Disease variant; Endoplasmic reticulum;
KW Epilepsy; Intellectual disability; Lipid metabolism; Magnesium; Membrane;
KW Metal-binding; Reference proteome; Retinitis pigmentosa; Transferase.
FT CHAIN 1..333
FT /note="Dehydrodolichyl diphosphate synthase complex subunit
FT DHDDS"
FT /id="PRO_0000123749"
FT BINDING 34
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:32817466"
FT BINDING 38
FT /ligand="isopentenyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:128769"
FT /evidence="ECO:0000269|PubMed:32817466"
FT BINDING 85
FT /ligand="isopentenyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:128769"
FT /evidence="ECO:0000269|PubMed:32817466"
FT BINDING 205
FT /ligand="isopentenyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:128769"
FT /evidence="ECO:0000269|PubMed:32817466"
FT BINDING 211
FT /ligand="isopentenyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:128769"
FT /evidence="ECO:0000269|PubMed:32817466"
FT BINDING 213
FT /ligand="isopentenyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:128769"
FT /evidence="ECO:0000269|PubMed:32817466"
FT VAR_SEQ 109..147
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_010030"
FT VAR_SEQ 147..181
FT /note="KCFLNVCFAYTSRHEISNAVREMAWGVEQGLLDPS -> N (in isoform
FT 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045007"
FT VAR_SEQ 255
FT /note="Q -> QQ (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_010031"
FT VARIANT 37
FT /note="R -> H (in DEDSM; unknown pathological significance;
FT dbSNP:rs1553121073)"
FT /evidence="ECO:0000269|PubMed:29100083"
FT /id="VAR_080708"
FT VARIANT 42
FT /note="K -> E (in RP59; 5-fold reduction in catalytic
FT activity and reduced affinity for FPP but not for IPP.;
FT dbSNP:rs147394623)"
FT /evidence="ECO:0000269|PubMed:21295283,
FT ECO:0000269|PubMed:28842490"
FT /id="VAR_065356"
FT VARIANT 95
FT /note="D -> N (found in a patient with progressive
FT myoclonus epilepsy; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:33798445"
FT /id="VAR_085034"
FT VARIANT 205
FT /note="R -> Q (found in a patient with progressive
FT myoclonus epilepsy; unknown pathological significance;
FT dbSNP:rs1557447255)"
FT /evidence="ECO:0000269|PubMed:33798445"
FT /id="VAR_085035"
FT VARIANT 211
FT /note="R -> Q (in DEDSM; also found in a patient with
FT progressive myoclonus epilepsy and developmental delay;
FT unknown pathological significance; dbSNP:rs1553122926)"
FT /evidence="ECO:0000269|PubMed:29100083,
FT ECO:0000269|PubMed:33798445"
FT /id="VAR_080709"
FT VARIANT 253
FT /note="V -> M (in dbSNP:rs3816539)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:20736409"
FT /id="VAR_028088"
FT MUTAGEN 12
FT /note="W->A: Markedly decreases phosphatidylinositol-
FT mediated activation of cis-prenyltransferase activity
FT resulting in products with longer chain length; when
FT associated with A-15 and A-19."
FT /evidence="ECO:0000269|PubMed:32817466"
FT MUTAGEN 15
FT /note="F->A: Markedly decreases phosphatidylinositol-
FT mediated activation of cis-prenyltransferase activity
FT resulting in products with longer chain length; when
FT associated with A-12 and A-19."
FT /evidence="ECO:0000269|PubMed:32817466"
FT MUTAGEN 19
FT /note="I->A: Markedly decreases phosphatidylinositol-
FT mediated activation of cis-prenyltransferase activity
FT resulting in products with longer chain length; when
FT associated with A-12 and A-15."
FT /evidence="ECO:0000269|PubMed:32817466"
FT MUTAGEN 106..109
FT /note="Missing: Affects chain elongation resulting in
FT shorter products."
FT /evidence="ECO:0000269|PubMed:32817466"
FT MUTAGEN 306
FT /note="R->A: Delays cell growth; when associated with A-313
FT and A-317."
FT /evidence="ECO:0000269|PubMed:32817466"
FT MUTAGEN 313
FT /note="F->A: Delays cell growth; when associated with A-306
FT and A-317."
FT /evidence="ECO:0000269|PubMed:32817466"
FT MUTAGEN 317
FT /note="L->A: Delays cell growth; when associated with A-306
FT and A-313."
FT /evidence="ECO:0000269|PubMed:32817466"
FT CONFLICT 151
FT /note="N -> Y (in Ref. 3; BAB14439)"
FT /evidence="ECO:0000305"
FT CONFLICT 277
FT /note="V -> E (in Ref. 6; AAH34152)"
FT /evidence="ECO:0000305"
FT TURN 2..4
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 11..20
FT /evidence="ECO:0007829|PDB:6Z1N"
FT STRAND 27..32
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 36..42
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 47..67
FT /evidence="ECO:0007829|PDB:6Z1N"
FT STRAND 72..79
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 80..84
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 87..103
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 110..113
FT /evidence="ECO:0007829|PDB:6Z1N"
FT STRAND 116..122
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 124..126
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 129..142
FT /evidence="ECO:0007829|PDB:6Z1N"
FT STRAND 147..156
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 158..174
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 180..182
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 185..190
FT /evidence="ECO:0007829|PDB:6Z1N"
FT TURN 193..196
FT /evidence="ECO:0007829|PDB:6Z1N"
FT STRAND 201..205
FT /evidence="ECO:0007829|PDB:6Z1N"
FT STRAND 214..216
FT /evidence="ECO:0007829|PDB:6Z1N"
FT TURN 217..222
FT /evidence="ECO:0007829|PDB:6Z1N"
FT STRAND 223..227
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 232..234
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 237..282
FT /evidence="ECO:0007829|PDB:6Z1N"
FT STRAND 283..285
FT /evidence="ECO:0007829|PDB:6Z1N"
FT HELIX 294..322
FT /evidence="ECO:0007829|PDB:6Z1N"
SQ SEQUENCE 333 AA; 38657 MW; 12EF3A15437A2583 CRC64;
MSWIKEGELS LWERFCANII KAGPMPKHIA FIMDGNRRYA KKCQVERQEG HSQGFNKLAE
TLRWCLNLGI LEVTVYAFSI ENFKRSKSEV DGLMDLARQK FSRLMEEKEK LQKHGVCIRV
LGDLHLLPLD LQELIAQAVQ ATKNYNKCFL NVCFAYTSRH EISNAVREMA WGVEQGLLDP
SDISESLLDK CLYTNRSPHP DILIRTSGEV RLSDFLLWQT SHSCLVFQPV LWPEYTFWNL
FEAILQFQMN HSVLQKARDM YAEERKRQQL ERDQATVTEQ LLREGLQASG DAQLRRTRLH
KLSARREERV QGFLQALELK RADWLARLGT ASA
