DLL1_HUMAN
ID DLL1_HUMAN Reviewed; 723 AA.
AC O00548; B2RAK7; B5M0B3; Q9NU41; Q9UJV2;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 200.
DE RecName: Full=Delta-like protein 1 {ECO:0000305};
DE AltName: Full=Drosophila Delta homolog 1;
DE Short=Delta1;
DE Short=H-Delta-1;
DE Flags: Precursor;
GN Name=DLL1 {ECO:0000312|HGNC:HGNC:2908}; ORFNames=UNQ146/PRO172;
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).
RX PubMed=10079256; DOI=10.1016/s0002-9440(10)65325-4;
RA Gray G.E., Mann R.S., Mitsiadis E., Henrique D., Carcangiu M.-L., Banks A.,
RA Leiman J., Ward D., Ish-Horowitz D., Artavanis-Tsakonas S.;
RT "Human ligands of the Notch receptor.";
RL Am. J. Pathol. 154:785-794(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=10688816;
RA Han W., Ye Q., Moore M.A.S.;
RT "A soluble form of human Delta-like-1 inhibits differentiation of
RT hematopoietic progenitor cells.";
RL Blood 95:1616-1625(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=19906316; DOI=10.1186/1471-2164-10-518;
RA Wang P., Yu P., Gao P., Shi T., Ma D.;
RT "Discovery of novel human transcript variants by analysis of intronic
RT single-block EST with polyadenylation site.";
RL BMC Genomics 10:518-518(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Oda T., Chandrasekharappa S.C.;
RT "Human Delta 1 gene sequence.";
RL Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [8]
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 [9]
RP FUNCTION.
RX PubMed=11006133; DOI=10.1006/bbrc.2000.3469;
RA Shimizu K., Chiba S., Saito T., Kumano K., Hirai H.;
RT "Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and
RT Notch3 receptors.";
RL Biochem. Biophys. Res. Commun. 276:385-389(2000).
RN [10]
RP FUNCTION.
RX PubMed=11581320; DOI=10.1084/jem.194.7.991;
RA Jaleco A.C., Neves H., Hooijberg E., Gameiro P., Clode N., Haury M.,
RA Henrique D., Parreira L.;
RT "Differential effects of Notch ligands Delta-1 and Jagged-1 in human
RT lymphoid differentiation.";
RL J. Exp. Med. 194:991-1001(2001).
RN [11]
RP INTERACTION WITH MAGI1; MAGI2; MAGI3 AND MPDZ.
RX PubMed=15509766; DOI=10.1242/dev.01417;
RA Wright G.J., Leslie J.D., Ariza-McNaughton L., Lewis J.;
RT "Delta proteins and MAGI proteins: an interaction of Notch ligands with
RT intracellular scaffolding molecules and its significance for zebrafish
RT development.";
RL Development 131:5659-5669(2004).
RN [12]
RP INTERACTION WITH SYNJ2BP.
RX PubMed=24025447; DOI=10.1161/circresaha.113.301686;
RA Adam M.G., Berger C., Feldner A., Yang W.J., Wuestehube-Lausch J.,
RA Herberich S.E., Pinder M., Gesierich S., Hammes H.P., Augustin H.G.,
RA Fischer A.;
RT "Synaptojanin-2 binding protein stabilizes the Notch ligands DLL1 and DLL4
RT and inhibits sprouting angiogenesis.";
RL Circ. Res. 113:1206-1218(2013).
RN [13]
RP INTERACTION WITH NOTCH2NLB.
RX PubMed=29856955; DOI=10.1016/j.cell.2018.03.067;
RA Suzuki I.K., Gacquer D., Van Heurck R., Kumar D., Wojno M., Bilheu A.,
RA Herpoel A., Lambert N., Cheron J., Polleux F., Detours V.,
RA Vanderhaeghen P.;
RT "Human-specific NOTCH2NL genes expand cortical neurogenesis through
RT Delta/Notch regulation.";
RL Cell 173:1370-1384(2018).
RN [14]
RP VARIANTS NEDBAS ILE-GLY-GLY-GLN-18 INS; 19-VAL--VAL-723 DEL;
RP 77-CYS--VAL-723 DEL; PHE-179; 498-GLU--VAL-723 DEL AND 509-ARG--VAL-723
RP DEL.
RX PubMed=31353024; DOI=10.1016/j.ajhg.2019.07.002;
RA Fischer-Zirnsak B., Segebrecht L., Schubach M., Charles P., Alderman E.,
RA Brown K., Cadieux-Dion M., Cartwright T., Chen Y., Costin C., Fehr S.,
RA Fitzgerald K.M., Fleming E., Foss K., Ha T., Hildebrand G., Horn D.,
RA Liu S., Marco E.J., McDonald M., McWalter K., Race S., Rush E.T., Si Y.,
RA Saunders C., Slavotinek A., Stockler-Ipsiroglu S., Telegrafi A.,
RA Thiffault I., Torti E., Tsai A.C., Wang X., Zafar M., Keren B., Kornak U.,
RA Boerkoel C.F., Mirzaa G., Ehmke N.;
RT "Haploinsufficiency of the Notch Ligand DLL1 Causes Variable
RT Neurodevelopmental Disorders.";
RL Am. J. Hum. Genet. 105:631-639(2019).
CC -!- FUNCTION: Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3
CC receptors that binds the extracellular domain (ECD) of Notch receptor
CC in a cis and trans fashion manner (PubMed:11006133). Following
CC transinteraction, ligand cells produce mechanical force that depends of
CC a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1
CC interaction, and actin polymerisation; these events promote Notch
CC receptor extracellular domain (NECD) transendocytosis and triggers
CC Notch signaling through induction of cleavage, hyperphosphorylation,
CC and nuclear accumulation of the intracellular domain of Notch receptors
CC (NICD) (By similarity). Is required for embryonic development and
CC maintenance of adult stem cells in many different tissues and immune
CC systeme; the DLL1-induced Notch signaling is mediated through an
CC intercellular communication that regulates cell lineage, cell
CC specification, cell patterning and morphogenesis through effects on
CC differentiation and proliferation (PubMed:11581320). Plays a role in
CC brain development at different level, namely by regulating neuronal
CC differentiation of neural precursor cells via cell-cell interaction,
CC most likely through the lateral inhibitory system in an endogenous
CC level dependent-manner. During neocortex development, Dll1-Notch
CC signaling transmission is mediated by dynamic interactions between
CC intermediate neurogenic progenitors and radial glia; the cell-cell
CC interactions are mediated via dynamic and transient elongation
CC processes, likely to reactivate/maintain Notch activity in neighboring
CC progenitors, and coordinate progenitor cell division and
CC differentiation across radial and zonal boundaries. During cerebellar
CC development, regulates Bergmann glial monolayer formation and its
CC morphological maturation through a Notch signaling pathway. At the
CC retina and spinal cord level, regulates neurogenesis by preventing the
CC premature differentiation of neural progenitors and also by maintaining
CC progenitors in spinal cord through Notch signaling pathway. Also
CC controls neurogenesis of the neural tube in a progenitor domain-
CC specific fashion along the dorsoventral axis. Maintains quiescence of
CC neural stem cells and plays a role as a fate determinant that
CC segregates asymmetrically to one daughter cell during neural stem cells
CC mitosis, resulting in neuronal differentiation in Dll1-inheriting cell.
CC Plays a role in immune systeme development, namely the development of
CC all T-cells and marginal zone (MZ) B-cells (By similarity). Blocks the
CC differentiation of progenitor cells into the B-cell lineage while
CC promoting the emergence of a population of cells with the
CC characteristics of a T-cell/NK-cell precursor (PubMed:11581320). Also
CC plays a role during muscle development. During early development,
CC inhibits myoblasts differentiation from the medial dermomyotomal lip
CC and later regulates progenitor cell differentiation. Directly modulates
CC cell adhesion and basal lamina formation in satellite cells through
CC Notch signaling. Maintains myogenic progenitors pool by suppressing
CC differentiation through down-regulation of MYOD1 and is required for
CC satellite cell homing and PAX7 expression. During craniofacial and
CC trunk myogenesis suppresses differentiation of cranial mesoderm-derived
CC and somite-derived muscle via MYOD1 regulation but in cranial mesoderm-
CC derived progenitors, is neither required for satellite cell homing nor
CC for PAX7 expression. Also plays a role during pancreatic cell
CC development. During type B pancreatic cell development, may be involved
CC in the initiation of proximodistal patterning in the early pancreatic
CC epithelium. Stimulates multipotent pancreatic progenitor cells
CC proliferation and pancreatic growth by maintaining HES1 expression and
CC PTF1A protein levels. During fetal stages of development, is required
CC to maintain arterial identity and the responsiveness of arterial
CC endothelial cells for VEGFA through regulation of KDR activation and
CC NRP1 expression. Controls sprouting angiogenesis and subsequent
CC vertical branch formation througth regulation on tip cell
CC differentiation. Negatively regulates goblet cell differentiation in
CC intestine and controls secretory fat commitment through lateral
CC inhibition in small intestine. Plays a role during inner ear
CC development; negatively regulates auditory hair cell differentiation.
CC Plays a role during nephron development through Notch signaling
CC pathway. Regulates growth, blood pressure and energy homeostasis (By
CC similarity). {ECO:0000250|UniProtKB:P97677,
CC ECO:0000250|UniProtKB:Q61483, ECO:0000269|PubMed:11006133,
CC ECO:0000269|PubMed:11581320}.
CC -!- SUBUNIT: Homodimer. Interacts with TJP1. Interacts with MAGI1 (via PDZ
CC domain); forms a complex with CTNNB1 and CDH2 and promotes recruitment
CC to the adherens junction and stabilization on the cell surface.
CC Interacts with PSEN1; undergoes a presenilin-dependent gamma-secretase
CC cleavage that releases a Dll1-intracellular form. Interacts with MFAP5.
CC Interacts with MIB1. Interacts with NEURL1B; leads to ubiquitination.
CC Interacts with NEURL1 (By similarity). Interacts with SYNJ2BP; enhances
CC DLL1 protein stability, and promotes Notch signaling in endothelial
CC cells (PubMed:24025447). Interacts with MAGI1, MAGI2, MAGI3 and MPDZ
CC (PubMed:15509766). Interacts (via ubiquitin) with EPN1 (via IUM
CC domain); binding with NOTCH1 attached to neighboring cell, promotes
CC ligand ubiquitination and EPN1 interaction, leading to NECD
CC transendocytosis and Notch signaling. Interacts with NOTCH1 (By
CC similarity) (PubMed:15509766, PubMed:24025447). Interacts with
CC NOTCH2NLB; leading to promote Notch signaling pathway in a cell-
CC autonomous manner through inhibition of cis DLL1-NOTCH2 interactions
CC (PubMed:29856955). {ECO:0000250|UniProtKB:P97677,
CC ECO:0000250|UniProtKB:Q61483, ECO:0000269|PubMed:15509766,
CC ECO:0000269|PubMed:24025447, ECO:0000269|PubMed:29856955}.
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000250|UniProtKB:Q61483}; Single-pass type I membrane protein
CC {ECO:0000250|UniProtKB:Q61483}. Cell junction, adherens junction
CC {ECO:0000250|UniProtKB:Q61483}. Membrane raft
CC {ECO:0000250|UniProtKB:Q61483}. Note=Distributed around adherens
CC junction in the apical endfeet through interactions with MAGI1.
CC {ECO:0000250|UniProtKB:Q61483}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O00548-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O00548-2; Sequence=VSP_057186, VSP_057187;
CC -!- TISSUE SPECIFICITY: Expressed in heart and pancreas, with lower
CC expression in brain and muscle and almost no expression in placenta,
CC lung, liver and kidney.
CC -!- PTM: Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis
CC and subsequent degradation (By similarity). Ubiquitinated; promotes
CC recycling back to the plasma membrane and confers a strong affinity for
CC NOTCH1. Multi-ubiquitination of LYS-613 by MIB1 promotes both cis and
CC trans-interaction with NOTCH1, as well as activation of Notch
CC signaling. Ubiquitinated by NEURL1B (By similarity).
CC {ECO:0000250|UniProtKB:P10041, ECO:0000250|UniProtKB:Q61483}.
CC -!- PTM: Phosphorylated in a membrane association-dependent manner.
CC Phosphorylation at Ser-697 requires the presence of Ser-694, whereas
CC phosphorylation at Ser-694 occurs independently of the other site.
CC Phosphorylation is required for full ligand activity in vitro and
CC affects surface presentation, ectodomain shedding, and endocytosis.
CC {ECO:0000250|UniProtKB:Q61483}.
CC -!- PTM: O-fucosylated. Can be elongated to a disaccharide by MFNG.
CC {ECO:0000250|UniProtKB:P97677}.
CC -!- DISEASE: Neurodevelopmental disorder with non-specific brain
CC abnormalities and with or without seizures (NEDBAS) [MIM:618709]: An
CC autosomal dominant disorder characterized by developmental delay,
CC intellectual disability, seizures, autism spectrum disorder, behavioral
CC abnormalities, and variable non-specific brain malformations.
CC {ECO:0000269|PubMed:31353024}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
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DR EMBL; AF003522; AAB61286.1; -; mRNA.
DR EMBL; AF196571; AAF05834.1; -; mRNA.
DR EMBL; EU927387; ACH57449.1; -; mRNA.
DR EMBL; AF222310; AAG09716.1; -; Genomic_DNA.
DR EMBL; AY358892; AAQ89251.1; -; mRNA.
DR EMBL; AK314234; BAG36904.1; -; mRNA.
DR EMBL; AL078605; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471051; EAW47425.1; -; Genomic_DNA.
DR CCDS; CCDS5313.1; -. [O00548-1]
DR RefSeq; NP_005609.3; NM_005618.3. [O00548-1]
DR PDB; 4XBM; X-ray; 3.20 A; A/B=21-545.
DR PDBsum; 4XBM; -.
DR AlphaFoldDB; O00548; -.
DR SMR; O00548; -.
DR BioGRID; 118391; 23.
DR CORUM; O00548; -.
DR IntAct; O00548; 1.
DR STRING; 9606.ENSP00000355718; -.
DR GlyGen; O00548; 1 site.
DR iPTMnet; O00548; -.
DR PhosphoSitePlus; O00548; -.
DR BioMuta; DLL1; -.
DR EPD; O00548; -.
DR MassIVE; O00548; -.
DR PaxDb; O00548; -.
DR PeptideAtlas; O00548; -.
DR PRIDE; O00548; -.
DR ProteomicsDB; 47965; -. [O00548-1]
DR ABCD; O00548; 5 sequenced antibodies.
DR Antibodypedia; 20091; 564 antibodies from 41 providers.
DR DNASU; 28514; -.
DR Ensembl; ENST00000366756.4; ENSP00000355718.3; ENSG00000198719.9. [O00548-1]
DR Ensembl; ENST00000616526.2; ENSP00000480905.1; ENSG00000275555.2. [O00548-1]
DR GeneID; 28514; -.
DR KEGG; hsa:28514; -.
DR MANE-Select; ENST00000366756.4; ENSP00000355718.3; NM_005618.4; NP_005609.3.
DR UCSC; uc003qxm.4; human. [O00548-1]
DR CTD; 28514; -.
DR DisGeNET; 28514; -.
DR GeneCards; DLL1; -.
DR GeneReviews; DLL1; -.
DR HGNC; HGNC:2908; DLL1.
DR HPA; ENSG00000198719; Tissue enhanced (lymphoid).
DR MalaCards; DLL1; -.
DR MIM; 606582; gene.
DR MIM; 618709; phenotype.
DR neXtProt; NX_O00548; -.
DR OpenTargets; ENSG00000198719; -.
DR Orphanet; 93925; Alobar holoprosencephaly.
DR Orphanet; 178469; Autosomal dominant non-syndromic intellectual disability.
DR Orphanet; 93924; Lobar holoprosencephaly.
DR Orphanet; 280200; Microform holoprosencephaly.
DR Orphanet; 93926; Midline interhemispheric variant of holoprosencephaly.
DR Orphanet; 220386; Semilobar holoprosencephaly.
DR Orphanet; 280195; Septopreoptic holoprosencephaly.
DR PharmGKB; PA27364; -.
DR VEuPathDB; HostDB:ENSG00000198719; -.
DR eggNOG; KOG1217; Eukaryota.
DR GeneTree; ENSGT00940000159781; -.
DR HOGENOM; CLU_012574_1_0_1; -.
DR InParanoid; O00548; -.
DR OMA; ATCHQRD; -.
DR OrthoDB; 406049at2759; -.
DR PhylomeDB; O00548; -.
DR TreeFam; TF351835; -.
DR PathwayCommons; O00548; -.
DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus.
DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants.
DR Reactome; R-HSA-2660826; Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant.
DR Reactome; R-HSA-2691232; Constitutive Signaling by NOTCH1 HD Domain Mutants.
DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants.
DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-HSA-9022702; MECP2 regulates transcription of neuronal ligands.
DR SignaLink; O00548; -.
DR SIGNOR; O00548; -.
DR BioGRID-ORCS; 28514; 10 hits in 1071 CRISPR screens.
DR ChiTaRS; DLL1; human.
DR GeneWiki; Delta-like_1; -.
DR GenomeRNAi; 28514; -.
DR Pharos; O00548; Tbio.
DR PRO; PR:O00548; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; O00548; protein.
DR Bgee; ENSG00000198719; Expressed in spleen and 94 other tissues.
DR ExpressionAtlas; O00548; baseline and differential.
DR Genevisible; O00548; HS.
DR GO; GO:0005912; C:adherens junction; ISS:UniProtKB.
DR GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; NAS:UniProtKB.
DR GO; GO:0045121; C:membrane raft; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005112; F:Notch binding; IPI:UniProtKB.
DR GO; GO:0097110; F:scaffold protein binding; IEA:Ensembl.
DR GO; GO:0030957; F:Tat protein binding; IPI:UniProtKB.
DR GO; GO:0014002; P:astrocyte development; ISS:UniProtKB.
DR GO; GO:0030154; P:cell differentiation; TAS:UniProtKB.
DR GO; GO:0001709; P:cell fate determination; NAS:UniProtKB.
DR GO; GO:0021688; P:cerebellar molecular layer formation; ISS:UniProtKB.
DR GO; GO:0021693; P:cerebellar Purkinje cell layer structural organization; ISS:UniProtKB.
DR GO; GO:0072583; P:clathrin-dependent endocytosis; ISS:UniProtKB.
DR GO; GO:0007386; P:compartment pattern specification; IEA:Ensembl.
DR GO; GO:0007368; P:determination of left/right symmetry; ISS:BHF-UCL.
DR GO; GO:0097102; P:endothelial tip cell fate specification; ISS:UniProtKB.
DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB.
DR GO; GO:0001947; P:heart looping; ISS:BHF-UCL.
DR GO; GO:0030097; P:hemopoiesis; NAS:UniProtKB.
DR GO; GO:0002085; P:inhibition of neuroepithelial cell differentiation; IEA:Ensembl.
DR GO; GO:0042491; P:inner ear auditory receptor cell differentiation; IEA:Ensembl.
DR GO; GO:0046331; P:lateral inhibition; ISS:UniProtKB.
DR GO; GO:0070986; P:left/right axis specification; IEA:Ensembl.
DR GO; GO:0072070; P:loop of Henle development; IEA:Ensembl.
DR GO; GO:0002315; P:marginal zone B cell differentiation; ISS:UniProtKB.
DR GO; GO:0030099; P:myeloid cell differentiation; IEA:Ensembl.
DR GO; GO:2000726; P:negative regulation of cardiac muscle cell differentiation; IEA:Ensembl.
DR GO; GO:0045596; P:negative regulation of cell differentiation; ISS:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0045605; P:negative regulation of epidermal cell differentiation; ISS:UniProtKB.
DR GO; GO:0030857; P:negative regulation of epithelial cell differentiation; ISS:UniProtKB.
DR GO; GO:0034351; P:negative regulation of glial cell apoptotic process; ISS:UniProtKB.
DR GO; GO:0045611; P:negative regulation of hemocyte differentiation; IEA:Ensembl.
DR GO; GO:0045608; P:negative regulation of inner ear auditory receptor cell differentiation; IEA:Ensembl.
DR GO; GO:0032693; P:negative regulation of interleukin-10 production; IMP:UniProtKB.
DR GO; GO:0045638; P:negative regulation of myeloid cell differentiation; IEA:Ensembl.
DR GO; GO:0045662; P:negative regulation of myoblast differentiation; ISS:UniProtKB.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; ISS:UniProtKB.
DR GO; GO:0045746; P:negative regulation of Notch signaling pathway; IBA:GO_Central.
DR GO; GO:0072006; P:nephron development; ISS:UniProtKB.
DR GO; GO:0060563; P:neuroepithelial cell differentiation; IEA:Ensembl.
DR GO; GO:0048665; P:neuron fate specification; ISS:UniProtKB.
DR GO; GO:0097150; P:neuronal stem cell population maintenance; IEP:UniProtKB.
DR GO; GO:0007219; P:Notch signaling pathway; IMP:UniProtKB.
DR GO; GO:0060853; P:Notch signaling pathway involved in arterial endothelial cell fate commitment; ISS:UniProtKB.
DR GO; GO:0035265; P:organ growth; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:UniProtKB.
DR GO; GO:0045807; P:positive regulation of endocytosis; ISS:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0045747; P:positive regulation of Notch signaling pathway; ISS:UniProtKB.
DR GO; GO:0048633; P:positive regulation of skeletal muscle tissue growth; ISS:UniProtKB.
DR GO; GO:1903672; P:positive regulation of sprouting angiogenesis; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR GO; GO:0072014; P:proximal tubule development; IEA:Ensembl.
DR GO; GO:0009954; P:proximal/distal pattern formation; ISS:UniProtKB.
DR GO; GO:0008217; P:regulation of blood pressure; ISS:UniProtKB.
DR GO; GO:0030155; P:regulation of cell adhesion; TAS:UniProtKB.
DR GO; GO:0051302; P:regulation of cell division; ISS:UniProtKB.
DR GO; GO:0040008; P:regulation of growth; ISS:UniProtKB.
DR GO; GO:0050767; P:regulation of neurogenesis; ISS:UniProtKB.
DR GO; GO:0048631; P:regulation of skeletal muscle tissue growth; ISS:UniProtKB.
DR GO; GO:0014807; P:regulation of somitogenesis; ISS:UniProtKB.
DR GO; GO:1900746; P:regulation of vascular endothelial growth factor signaling pathway; ISS:UniProtKB.
DR GO; GO:0060041; P:retina development in camera-type eye; ISS:UniProtKB.
DR GO; GO:0060042; P:retina morphogenesis in camera-type eye; ISS:UniProtKB.
DR GO; GO:0048630; P:skeletal muscle tissue growth; ISS:UniProtKB.
DR GO; GO:0098773; P:skin epidermis development; ISS:UniProtKB.
DR GO; GO:0001757; P:somite specification; IEA:Ensembl.
DR GO; GO:0001756; P:somitogenesis; ISS:UniProtKB.
DR GO; GO:0021510; P:spinal cord development; ISS:UniProtKB.
DR GO; GO:0003323; P:type B pancreatic cell development; ISS:UniProtKB.
DR InterPro; IPR001774; DSL.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR013032; EGF-like_CS.
DR InterPro; IPR000742; EGF-like_dom.
DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR InterPro; IPR018097; EGF_Ca-bd_CS.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR011651; Notch_ligand_N.
DR Pfam; PF01414; DSL; 1.
DR Pfam; PF00008; EGF; 5.
DR Pfam; PF12661; hEGF; 1.
DR Pfam; PF07657; MNNL; 1.
DR SMART; SM00051; DSL; 1.
DR SMART; SM00181; EGF; 8.
DR SMART; SM00179; EGF_CA; 6.
DR SUPFAM; SSF57184; SSF57184; 2.
DR PROSITE; PS00010; ASX_HYDROXYL; 3.
DR PROSITE; PS51051; DSL; 1.
DR PROSITE; PS00022; EGF_1; 8.
DR PROSITE; PS01186; EGF_2; 8.
DR PROSITE; PS50026; EGF_3; 7.
DR PROSITE; PS01187; EGF_CA; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Autism spectrum disorder;
KW Cell junction; Cell membrane; Developmental protein; Differentiation;
KW Disulfide bond; EGF-like domain; Epilepsy; Glycoprotein;
KW Intellectual disability; Isopeptide bond; Membrane;
KW Notch signaling pathway; Phosphoprotein; Reference proteome; Repeat;
KW Signal; Transmembrane; Transmembrane helix; Ubl conjugation.
FT SIGNAL 1..17
FT /evidence="ECO:0000255"
FT CHAIN 18..723
FT /note="Delta-like protein 1"
FT /id="PRO_0000007506"
FT TOPO_DOM 18..545
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 546..568
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 569..723
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 177..221
FT /note="DSL"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00377"
FT DOMAIN 226..254
FT /note="EGF-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 257..285
FT /note="EGF-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 292..325
FT /note="EGF-like 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 332..363
FT /note="EGF-like 4; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 370..402
FT /note="EGF-like 5"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 409..440
FT /note="EGF-like 6"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 447..478
FT /note="EGF-like 7; calcium-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT DOMAIN 485..516
FT /note="EGF-like 8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076"
FT REGION 653..702
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 720..723
FT /note="Interaction with MAGI1"
FT /evidence="ECO:0000250|UniProtKB:Q61483"
FT MOD_RES 694
FT /note="Phosphoserine; by PKB"
FT /evidence="ECO:0000250|UniProtKB:Q61483"
FT MOD_RES 697
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q61483"
FT CARBOHYD 477
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 179..188
FT /evidence="ECO:0000250"
FT DISULFID 192..204
FT /evidence="ECO:0000250"
FT DISULFID 212..221
FT /evidence="ECO:0000250"
FT DISULFID 226..237
FT /evidence="ECO:0000250"
FT DISULFID 230..243
FT /evidence="ECO:0000250"
FT DISULFID 245..254
FT /evidence="ECO:0000250"
FT DISULFID 257..268
FT /evidence="ECO:0000250"
FT DISULFID 263..274
FT /evidence="ECO:0000250"
FT DISULFID 276..285
FT /evidence="ECO:0000250"
FT DISULFID 292..304
FT /evidence="ECO:0000250"
FT DISULFID 298..314
FT /evidence="ECO:0000250"
FT DISULFID 316..325
FT /evidence="ECO:0000250"
FT DISULFID 332..343
FT /evidence="ECO:0000250"
FT DISULFID 337..352
FT /evidence="ECO:0000250"
FT DISULFID 354..363
FT /evidence="ECO:0000250"
FT DISULFID 370..381
FT /evidence="ECO:0000250"
FT DISULFID 375..391
FT /evidence="ECO:0000250"
FT DISULFID 393..402
FT /evidence="ECO:0000250"
FT DISULFID 409..420
FT /evidence="ECO:0000250"
FT DISULFID 414..429
FT /evidence="ECO:0000250"
FT DISULFID 431..440
FT /evidence="ECO:0000250"
FT DISULFID 447..458
FT /evidence="ECO:0000250"
FT DISULFID 452..467
FT /evidence="ECO:0000250"
FT DISULFID 469..478
FT /evidence="ECO:0000250"
FT DISULFID 485..496
FT /evidence="ECO:0000250"
FT DISULFID 490..505
FT /evidence="ECO:0000250"
FT DISULFID 507..516
FT /evidence="ECO:0000250"
FT CROSSLNK 613
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q61483"
FT VAR_SEQ 224..247
FT /note="PICLPGCDEQHGFCDKPGECKCRV -> RESLGRHRWLTRPRTRTTRRDGAS
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:19906316"
FT /id="VSP_057186"
FT VAR_SEQ 248..723
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:19906316"
FT /id="VSP_057187"
FT VARIANT 18
FT /note="Q -> QIGGQ (in NEDBAS; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:31353024"
FT /id="VAR_083465"
FT VARIANT 19..723
FT /note="Missing (in NEDBAS)"
FT /evidence="ECO:0000269|PubMed:31353024"
FT /id="VAR_083466"
FT VARIANT 77..723
FT /note="Missing (in NEDBAS)"
FT /evidence="ECO:0000269|PubMed:31353024"
FT /id="VAR_083467"
FT VARIANT 179
FT /note="C -> F (in NEDBAS)"
FT /evidence="ECO:0000269|PubMed:31353024"
FT /id="VAR_083468"
FT VARIANT 444
FT /note="V -> M (in dbSNP:rs16901311)"
FT /id="VAR_048976"
FT VARIANT 498..723
FT /note="Missing (in NEDBAS)"
FT /evidence="ECO:0000269|PubMed:31353024"
FT /id="VAR_083469"
FT VARIANT 509..723
FT /note="Missing (in NEDBAS; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:31353024"
FT /id="VAR_083470"
FT CONFLICT 498
FT /note="E -> Q (in Ref. 2; AAF05834)"
FT /evidence="ECO:0000305"
FT CONFLICT 502
FT /note="R -> G (in Ref. 1; AAB61286, 2; AAF05834 and 3;
FT AAG09716)"
FT /evidence="ECO:0000305"
FT CONFLICT 510
FT /note="G -> S (in Ref. 2; AAF05834)"
FT /evidence="ECO:0000305"
FT STRAND 23..30
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 57..66
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 78..83
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 88..91
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 108..112
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 118..128
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 143..152
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 156..166
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 169..179
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 183..185
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 195..197
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 200..204
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 206..208
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 210..212
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 216..218
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 232..236
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 249..254
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 265..267
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 280..285
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 287..289
FT /evidence="ECO:0007829|PDB:4XBM"
FT HELIX 292..295
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 303..306
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 308..310
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 312..315
FT /evidence="ECO:0007829|PDB:4XBM"
FT TURN 322..325
FT /evidence="ECO:0007829|PDB:4XBM"
FT TURN 331..334
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 342..346
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 349..353
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 358..362
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 365..367
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 380..383
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 385..387
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 389..392
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 399..402
FT /evidence="ECO:0007829|PDB:4XBM"
FT HELIX 408..411
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 419..422
FT /evidence="ECO:0007829|PDB:4XBM"
FT STRAND 427..430
FT /evidence="ECO:0007829|PDB:4XBM"
SQ SEQUENCE 723 AA; 78056 MW; 094B8F235DFD899D CRC64;
MGSRCALALA VLSALLCQVW SSGVFELKLQ EFVNKKGLLG NRNCCRGGAG PPPCACRTFF
RVCLKHYQAS VSPEPPCTYG SAVTPVLGVD SFSLPDGGGA DSAFSNPIRF PFGFTWPGTF
SLIIEALHTD SPDDLATENP ERLISRLATQ RHLTVGEEWS QDLHSSGRTD LKYSYRFVCD
EHYYGEGCSV FCRPRDDAFG HFTCGERGEK VCNPGWKGPY CTEPICLPGC DEQHGFCDKP
GECKCRVGWQ GRYCDECIRY PGCLHGTCQQ PWQCNCQEGW GGLFCNQDLN YCTHHKPCKN
GATCTNTGQG SYTCSCRPGY TGATCELGID ECDPSPCKNG GSCTDLENSY SCTCPPGFYG
KICELSAMTC ADGPCFNGGR CSDSPDGGYS CRCPVGYSGF NCEKKIDYCS SSPCSNGAKC
VDLGDAYLCR CQAGFSGRHC DDNVDDCASS PCANGGTCRD GVNDFSCTCP PGYTGRNCSA
PVSRCEHAPC HNGATCHERG HRYVCECARG YGGPNCQFLL PELPPGPAVV DLTEKLEGQG
GPFPWVAVCA GVILVLMLLL GCAAVVVCVR LRLQKHRPPA DPCRGETETM NNLANCQREK
DISVSIIGAT QIKNTNKKAD FHGDHSADKN GFKARYPAVD YNLVQDLKGD DTAVRDAHSK
RDTKCQPQGS SGEEKGTPTT LRGGEASERK RPDSGCSTSK DTKYQSVYVI SEEKDECVIA
TEV
