DPH3_HUMAN
ID DPH3_HUMAN Reviewed; 82 AA.
AC Q96FX2;
DT 04-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Diphthamide biosynthesis protein 3 {ECO:0000305};
DE AltName: Full=CSL-type zinc finger-containing protein 2;
DE AltName: Full=DelGEF-interacting protein 1;
DE Short=DelGIP1;
GN Name=DPH3; Synonyms=DESR1 {ECO:0000303|PubMed:14527407}, ZCSL2;
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), FUNCTION, SUBCELLULAR LOCATION,
RP TISSUE SPECIFICITY, AND INTERACTION WITH SERGEF.
RX PubMed=14980502; DOI=10.1016/j.yexcr.2003.09.033;
RA Sjoelinder M., Uhlmann J., Ponstingl H.;
RT "Characterisation of an evolutionary conserved protein interacting with the
RT putative guanine nucleotide exchange factor DelGEF and modulating
RT secretion.";
RL Exp. Cell Res. 294:68-76(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Teratocarcinoma;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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 TISSUE SPECIFICITY.
RX PubMed=14527407; DOI=10.1016/j.molcel.2003.08.003;
RA Liu S., Leppla S.H.;
RT "Retroviral insertional mutagenesis identifies a small protein required for
RT synthesis of diphthamide, the target of bacterial ADP-ribosylating
RT toxins.";
RL Mol. Cell 12:603-613(2003).
RN [5] {ECO:0007744|PDB:2JR7}
RP STRUCTURE BY NMR OF 1-81 IN COMPLEX WITH ZINC IONS.
RX PubMed=18214955; DOI=10.1002/prot.21915;
RA Wu F., Zhang J., Sun J., Huang H., Ji P., Chu W., Yu M., Yang F., Wu Z.,
RA Wu J., Shi Y.;
RT "Solution structure of human DESR1, a CSL zinc-binding protein.";
RL Proteins 71:514-518(2008).
CC -!- FUNCTION: Required for the first step of diphthamide biosynthesis, a
CC post-translational modification of histidine which occurs in elongation
CC factor 2. DPH1 and DPH2 transfer a 3-amino-3-carboxypropyl (ACP) group
CC from S-adenosyl-L-methionine (SAM) to a histidine residue, the reaction
CC is assisted by a reduction system comprising DPH3 and a NADH-dependent
CC reductase. Acts as an electron donor to reduce the Fe-S cluster in
CC DPH1-DPH2 keeping the [4Fe-4S] clusters in the active and reduced
CC state. Restores iron to DPH1-DPH2 iron-sulfur clusters which have
CC degraded from [4Fe-4S] to [3Fe-4S] by donating an iron atom to reform
CC [4Fe-4S] clusters, in a manner dependent on the presence of elongation
CC factor 2 and SAM. Associates with the elongator complex and is required
CC for tRNA Wobble base modifications mediated by the elongator complex.
CC The elongator complex is required for multiple tRNA modifications,
CC including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s 2U (5-
CC methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl
CC uridine). {ECO:0000250|UniProtKB:Q3E840}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=[3Fe-4S](1+)-[protein] + Fe(2+)-[Dph3] = [3Fe-4S](0)-[protein]
CC + Fe(3+)-[Dph3]; Xref=Rhea:RHEA:71235, Rhea:RHEA-COMP:17996,
CC Rhea:RHEA-COMP:17997, Rhea:RHEA-COMP:18002, Rhea:RHEA-COMP:18003,
CC ChEBI:CHEBI:29033, ChEBI:CHEBI:29034, ChEBI:CHEBI:33751,
CC ChEBI:CHEBI:47402, ChEBI:CHEBI:83228;
CC Evidence={ECO:0000250|UniProtKB:Q3E840};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 [3Fe-4S](0)-[protein] + 2 Fe(2+)-[Dph3] + NADH = 2 [4Fe-
CC 4S](1+)-[protein] + 2 [Dph3] + H(+) + NAD(+); Xref=Rhea:RHEA:71239,
CC Rhea:RHEA-COMP:17997, Rhea:RHEA-COMP:17998, Rhea:RHEA-COMP:18001,
CC Rhea:RHEA-COMP:18002, ChEBI:CHEBI:15378, ChEBI:CHEBI:29033,
CC ChEBI:CHEBI:33723, ChEBI:CHEBI:47402, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:83228;
CC Evidence={ECO:0000250|UniProtKB:Q3E840};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000250|UniProtKB:Q3E840};
CC -!- PATHWAY: Protein modification; peptidyl-diphthamide biosynthesis.
CC {ECO:0000305}.
CC -!- SUBUNIT: Component of the 2-(3-amino-3-carboxypropyl)histidine synthase
CC complex composed of DPH1, DPH2, DPH3 and a NADH-dependent reductase (By
CC similarity). Interacts with SERGEF (PubMed:14980502).
CC {ECO:0000250|UniProtKB:Q3E840, ECO:0000269|PubMed:14980502}.
CC -!- INTERACTION:
CC Q96FX2; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-465363, EBI-16439278;
CC Q96FX2; Q8WWB5: PIH1D2; NbExp=6; IntAct=EBI-465363, EBI-10232538;
CC Q96FX2; Q9UGK8: SERGEF; NbExp=7; IntAct=EBI-465363, EBI-465368;
CC Q96FX2; Q7Z4V0: ZNF438; NbExp=3; IntAct=EBI-465363, EBI-11962468;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14980502}. Nucleus
CC {ECO:0000269|PubMed:14980502}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q96FX2-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96FX2-2; Sequence=VSP_012411;
CC -!- TISSUE SPECIFICITY: Widely expressed with highest levels in small
CC intestine, spleen, thymus, heart, liver and lung.
CC {ECO:0000269|PubMed:14527407, ECO:0000269|PubMed:14980502}.
CC -!- DOMAIN: The DPH-type metal-binding (MB) domain can also bind zinc.
CC However, iron is the physiological binding partner as zinc binding
CC impairs the protein electron donor function.
CC {ECO:0000250|UniProtKB:Q3E840}.
CC -!- SIMILARITY: Belongs to the DPH3 family. {ECO:0000305}.
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DR EMBL; AK022970; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC010181; AAH10181.1; -; mRNA.
DR CCDS; CCDS2629.1; -. [Q96FX2-1]
DR CCDS; CCDS43058.1; -. [Q96FX2-2]
DR RefSeq; NP_001040899.1; NM_001047434.2. [Q96FX2-2]
DR RefSeq; NP_996662.1; NM_206831.2. [Q96FX2-1]
DR PDB; 2JR7; NMR; -; A=1-81.
DR PDBsum; 2JR7; -.
DR AlphaFoldDB; Q96FX2; -.
DR BMRB; Q96FX2; -.
DR SMR; Q96FX2; -.
DR BioGRID; 130097; 10.
DR IntAct; Q96FX2; 9.
DR STRING; 9606.ENSP00000419599; -.
DR PhosphoSitePlus; Q96FX2; -.
DR BioMuta; DPH3; -.
DR DMDM; 29611922; -.
DR EPD; Q96FX2; -.
DR jPOST; Q96FX2; -.
DR MassIVE; Q96FX2; -.
DR MaxQB; Q96FX2; -.
DR PaxDb; Q96FX2; -.
DR PeptideAtlas; Q96FX2; -.
DR PRIDE; Q96FX2; -.
DR ProteomicsDB; 76568; -. [Q96FX2-1]
DR ProteomicsDB; 76569; -. [Q96FX2-2]
DR Antibodypedia; 26896; 41 antibodies from 11 providers.
DR DNASU; 285381; -.
DR Ensembl; ENST00000383775.4; ENSP00000373285.4; ENSG00000154813.10. [Q96FX2-2]
DR Ensembl; ENST00000488423.2; ENSP00000419599.1; ENSG00000154813.10. [Q96FX2-1]
DR GeneID; 285381; -.
DR KEGG; hsa:285381; -.
DR MANE-Select; ENST00000488423.2; ENSP00000419599.1; NM_206831.3; NP_996662.1.
DR UCSC; uc003cau.4; human. [Q96FX2-1]
DR CTD; 285381; -.
DR DisGeNET; 285381; -.
DR GeneCards; DPH3; -.
DR HGNC; HGNC:27717; DPH3.
DR HPA; ENSG00000154813; Low tissue specificity.
DR MIM; 608959; gene.
DR neXtProt; NX_Q96FX2; -.
DR OpenTargets; ENSG00000154813; -.
DR PharmGKB; PA162384061; -.
DR VEuPathDB; HostDB:ENSG00000154813; -.
DR eggNOG; KOG2923; Eukaryota.
DR GeneTree; ENSGT00390000007225; -.
DR HOGENOM; CLU_155991_3_0_1; -.
DR InParanoid; Q96FX2; -.
DR OMA; IYDPDMF; -.
DR PhylomeDB; Q96FX2; -.
DR TreeFam; TF315102; -.
DR PathwayCommons; Q96FX2; -.
DR Reactome; R-HSA-5358493; Synthesis of diphthamide-EEF2.
DR SignaLink; Q96FX2; -.
DR UniPathway; UPA00559; -.
DR BioGRID-ORCS; 285381; 690 hits in 1050 CRISPR screens.
DR ChiTaRS; DPH3; human.
DR EvolutionaryTrace; Q96FX2; -.
DR GenomeRNAi; 285381; -.
DR Pharos; Q96FX2; Tdark.
DR PRO; PR:Q96FX2; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q96FX2; protein.
DR Bgee; ENSG00000154813; Expressed in ileal mucosa and 185 other tissues.
DR Genevisible; Q96FX2; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0008198; F:ferrous iron binding; ISS:UniProtKB.
DR GO; GO:0034986; F:iron chaperone activity; ISS:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; ISS:UniProtKB.
DR GO; GO:0050709; P:negative regulation of protein secretion; IDA:UniProtKB.
DR GO; GO:0017183; P:peptidyl-diphthamide biosynthetic process from peptidyl-histidine; ISS:UniProtKB.
DR GO; GO:0051099; P:positive regulation of binding; IDA:UniProtKB.
DR GO; GO:0002926; P:tRNA wobble base 5-methoxycarbonylmethyl-2-thiouridinylation; ISS:UniProtKB.
DR GO; GO:0002098; P:tRNA wobble uridine modification; IBA:GO_Central.
DR Gene3D; 3.10.660.10; -; 1.
DR InterPro; IPR044248; DPH3/4-like.
DR InterPro; IPR007872; DPH_MB_dom.
DR InterPro; IPR036671; DPH_MB_sf.
DR PANTHER; PTHR21454; PTHR21454; 1.
DR Pfam; PF05207; zf-CSL; 1.
DR SUPFAM; SSF144217; SSF144217; 1.
DR PROSITE; PS51074; DPH_MB; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Iron; Metal-binding;
KW Nucleus; Reference proteome.
FT CHAIN 1..82
FT /note="Diphthamide biosynthesis protein 3"
FT /id="PRO_0000082620"
FT DOMAIN 4..60
FT /note="DPH-type MB"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00456"
FT BINDING 26
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000305|PubMed:18214955,
FT ECO:0007744|PDB:2JR7"
FT BINDING 28
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000305|PubMed:18214955,
FT ECO:0007744|PDB:2JR7"
FT BINDING 48
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000305|PubMed:18214955,
FT ECO:0007744|PDB:2JR7"
FT BINDING 51
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000305|PubMed:18214955,
FT ECO:0007744|PDB:2JR7"
FT VAR_SEQ 36..60
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_012411"
FT STRAND 7..9
FT /evidence="ECO:0007829|PDB:2JR7"
FT TURN 10..12
FT /evidence="ECO:0007829|PDB:2JR7"
FT STRAND 13..15
FT /evidence="ECO:0007829|PDB:2JR7"
FT TURN 17..19
FT /evidence="ECO:0007829|PDB:2JR7"
FT STRAND 20..25
FT /evidence="ECO:0007829|PDB:2JR7"
FT STRAND 29..35
FT /evidence="ECO:0007829|PDB:2JR7"
FT HELIX 36..41
FT /evidence="ECO:0007829|PDB:2JR7"
FT STRAND 45..47
FT /evidence="ECO:0007829|PDB:2JR7"
FT TURN 49..51
FT /evidence="ECO:0007829|PDB:2JR7"
FT STRAND 54..58
FT /evidence="ECO:0007829|PDB:2JR7"
FT HELIX 61..64
FT /evidence="ECO:0007829|PDB:2JR7"
SQ SEQUENCE 82 AA; 9240 MW; 7AC8F3FFF8CE766C CRC64;
MAVFHDEVEI EDFQYDEDSE TYFYPCPCGD NFSITKEDLE NGEDVATCPS CSLIIKVIYD
KDQFVCGETV PAPSANKELV KC
