LOL2A_DANRE
ID LOL2A_DANRE Reviewed; 737 AA.
AC F1QQC3; A6MH30;
DT 13-JUN-2012, integrated into UniProtKB/Swiss-Prot.
DT 03-MAY-2011, sequence version 1.
DT 03-AUG-2022, entry version 70.
DE RecName: Full=Lysyl oxidase homolog 2A;
DE EC=1.4.3.13 {ECO:0000250|UniProtKB:Q9Y4K0};
DE AltName: Full=Lysyl oxidase-like protein 2A;
DE Flags: Precursor;
GN Name=loxl2a;
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=17543297; DOI=10.1016/j.ydbio.2007.04.029;
RA Gansner J.M., Mendelsohn B.A., Hultman K.A., Johnson S.L., Gitlin J.D.;
RT "Essential role of lysyl oxidases in notochord development.";
RL Dev. Biol. 307:202-213(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [3]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=21835952; DOI=10.1182/blood-2010-10-313296;
RA Bignon M., Pichol-Thievend C., Hardouin J., Malbouyres M., Brechot N.,
RA Nasciutti L., Barret A., Teillon J., Guillon E., Etienne E., Caron M.,
RA Joubert-Caron R., Monnot C., Ruggiero F., Muller L., Germain S.;
RT "Lysyl oxidase-like protein-2 regulates sprouting angiogenesis and type IV
RT collagen assembly in the endothelial basement membrane.";
RL Blood 118:3979-3989(2011).
RN [4]
RP FUNCTION, DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=25959397; DOI=10.1016/j.molcel.2015.04.012;
RA Iturbide A., Pascual-Reguant L., Fargas L., Cebria J.P., Alsina B.,
RA Garcia de Herreros A., Peiro S.;
RT "LOXL2 oxidizes methylated TAF10 and controls TFIID-dependent genes during
RT neural progenitor differentiation.";
RL Mol. Cell 58:755-766(2015).
CC -!- FUNCTION: Mediates the post-translational oxidative deamination of
CC lysine residues on target proteins leading to the formation of
CC deaminated lysine (allysine) (By similarity). Acts as a transcription
CC corepressor and specifically mediates deamination of trimethylated
CC 'Lys-4' of histone H3 (H3K4me3), a specific tag for epigenetic
CC transcriptional activation (By similarity). Shows no activity against
CC histone H3 when it is trimethylated on 'Lys-9' (H3K9me3) or 'Lys-27'
CC (H3K27me3) or when 'Lys-4' is monomethylated (H3K4me1) or dimethylated
CC (H3K4me2) (By similarity). Also mediates deamination of methylated
CC TAF10, a member of the transcription factor IID (TFIID) complex, which
CC induces release of TAF10 from promoters, leading to inhibition of
CC TFIID-dependent transcription (By similarity). LOXL2-mediated
CC deamination of TAF10 results in transcriptional repression of genes
CC required for embryonic stem cell pluripotency (By similarity). Involved
CC in epithelial to mesenchymal transition (EMT) and participates in
CC repression of E-cadherin, probably by mediating deamination of histone
CC H3 (By similarity). When secreted into the extracellular matrix,
CC promotes cross-linking of extracellular matrix proteins by mediating
CC oxidative deamination of peptidyl lysine residues in precursors to
CC fibrous collagen and elastin (By similarity). Acts as a regulator of
CC sprouting angiogenesis, probably via collagen IV scaffolding
CC (PubMed:21835952). Acts as a regulator of chondrocyte differentiation,
CC probably by regulating expression of factors that control chondrocyte
CC differentiation (By similarity). Required with loxl2b for correct
CC expression of Sox2 and for neural differentiation (PubMed:25959397).
CC {ECO:0000250|UniProtKB:P58022, ECO:0000250|UniProtKB:Q9Y4K0,
CC ECO:0000269|PubMed:21835952, ECO:0000269|PubMed:25959397}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + L-lysyl-[protein] + O2 = (S)-2-amino-6-oxohexanoyl-
CC [protein] + H2O2 + NH4(+); Xref=Rhea:RHEA:24544, Rhea:RHEA-COMP:9752,
CC Rhea:RHEA-COMP:12448, ChEBI:CHEBI:15377, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16240, ChEBI:CHEBI:28938, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:131803; EC=1.4.3.13;
CC Evidence={ECO:0000250|UniProtKB:Q9Y4K0};
CC -!- COFACTOR:
CC Name=Cu cation; Xref=ChEBI:CHEBI:23378;
CC Evidence={ECO:0000250|UniProtKB:Q9Y4K0};
CC -!- COFACTOR:
CC Name=lysine tyrosylquinone residue; Xref=ChEBI:CHEBI:20489;
CC Evidence={ECO:0000250|UniProtKB:Q9Y4K0};
CC Note=Contains 1 lysine tyrosylquinone. {ECO:0000250|UniProtKB:P33072,
CC ECO:0000250|UniProtKB:Q9Y4K0};
CC -!- SUBCELLULAR LOCATION: Secreted, extracellular space, extracellular
CC matrix, basement membrane {ECO:0000250|UniProtKB:Q9Y4K0}. Nucleus
CC {ECO:0000250|UniProtKB:Q9Y4K0}. Chromosome
CC {ECO:0000250|UniProtKB:Q9Y4K0}. Endoplasmic reticulum
CC {ECO:0000250|UniProtKB:Q9Y4K0}. Note=Associated with chromatin. It is
CC unclear how LOXL2 is nuclear as it contains a signal sequence and has
CC been shown to be secreted. However, a number of reports confirm its
CC intracellular location and its key role in transcription regulation.
CC {ECO:0000250|UniProtKB:Q9Y4K0}.
CC -!- DEVELOPMENTAL STAGE: Expression increases between 20 and 48 hours after
CC fertilization and is detected in sprouting intersegmental vessels
CC (PubMed:21835952). At 24 hours after fertilization, expressed
CC throughout the embryo with high levels in eye, mesencephalon and
CC hindbrain boundaries (PubMed:25959397). {ECO:0000269|PubMed:21835952,
CC ECO:0000269|PubMed:25959397}.
CC -!- PTM: The lysine tyrosylquinone cross-link (LTQ) is generated by
CC condensation of the epsilon-amino group of a lysine with a topaquinone
CC produced by oxidation of tyrosine. {ECO:0000250|UniProtKB:Q9Y4K0}.
CC -!- DISRUPTION PHENOTYPE: Morpholino knockdown in the embryo prevents the
CC formation of intersegmental blood vessels (PubMed:21835952). Morpholino
CC knockdown of loxl2a and loxl2b in the embryo results in increased
CC expression of Sox2 in the central nervous system, particularly in the
CC eye, hindbrain and spinal cord (PubMed:25959397). It also leads to
CC impaired neural differentiation with morphological defects in the brain
CC where the anterior brain is rounder than normal and the eyes present a
CC flatter curvature (PubMed:25959397). Embryo development is also
CC compromised (PubMed:25959397). {ECO:0000269|PubMed:21835952,
CC ECO:0000269|PubMed:25959397}.
CC -!- SIMILARITY: Belongs to the lysyl oxidase family. {ECO:0000305}.
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DR EMBL; EF030481; ABM86967.1; -; mRNA.
DR EMBL; BX294119; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_001092714.1; NM_001099244.1.
DR RefSeq; XP_009303525.1; XM_009305250.2.
DR AlphaFoldDB; F1QQC3; -.
DR SMR; F1QQC3; -.
DR STRING; 7955.ENSDARP00000064612; -.
DR PaxDb; F1QQC3; -.
DR Ensembl; ENSDART00000064613; ENSDARP00000064612; ENSDARG00000044010.
DR GeneID; 565508; -.
DR KEGG; dre:565508; -.
DR CTD; 565508; -.
DR ZFIN; ZDB-GENE-070818-1; loxl2a.
DR eggNOG; ENOG502QSX8; Eukaryota.
DR GeneTree; ENSGT00940000155874; -.
DR InParanoid; F1QQC3; -.
DR OMA; QSWVWHE; -.
DR OrthoDB; 815466at2759; -.
DR PhylomeDB; F1QQC3; -.
DR TreeFam; TF326061; -.
DR BRENDA; 1.4.3.13; 928.
DR PRO; PR:F1QQC3; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 10.
DR Bgee; ENSDARG00000044010; Expressed in liver and 28 other tissues.
DR ExpressionAtlas; F1QQC3; baseline.
DR GO; GO:0005604; C:basement membrane; ISS:UniProtKB.
DR GO; GO:0000785; C:chromatin; ISS:UniProtKB.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; IBA:GO_Central.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; IEA:InterPro.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0005507; F:copper ion binding; ISS:UniProtKB.
DR GO; GO:0004720; F:protein-lysine 6-oxidase activity; ISS:UniProtKB.
DR GO; GO:0005044; F:scavenger receptor activity; IEA:InterPro.
DR GO; GO:0030199; P:collagen fibril organization; ISS:UniProtKB.
DR GO; GO:0043542; P:endothelial cell migration; ISS:UniProtKB.
DR GO; GO:0001935; P:endothelial cell proliferation; ISS:UniProtKB.
DR GO; GO:0001837; P:epithelial to mesenchymal transition; ISS:UniProtKB.
DR GO; GO:0070828; P:heterochromatin organization; ISS:UniProtKB.
DR GO; GO:1902455; P:negative regulation of stem cell population maintenance; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0018057; P:peptidyl-lysine oxidation; ISS:UniProtKB.
DR GO; GO:0032332; P:positive regulation of chondrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0010718; P:positive regulation of epithelial to mesenchymal transition; ISS:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; ISS:UniProtKB.
DR GO; GO:0002040; P:sprouting angiogenesis; IMP:UniProtKB.
DR Gene3D; 3.10.250.10; -; 4.
DR InterPro; IPR001695; Lysyl_oxidase.
DR InterPro; IPR019828; Lysyl_oxidase_CS.
DR InterPro; IPR001190; SRCR.
DR InterPro; IPR017448; SRCR-like_dom.
DR InterPro; IPR036772; SRCR-like_dom_sf.
DR Pfam; PF01186; Lysyl_oxidase; 1.
DR Pfam; PF00530; SRCR; 4.
DR PRINTS; PR00074; LYSYLOXIDASE.
DR PRINTS; PR00258; SPERACTRCPTR.
DR SMART; SM00202; SR; 4.
DR SUPFAM; SSF56487; SSF56487; 4.
DR PROSITE; PS00926; LYSYL_OXIDASE; 1.
DR PROSITE; PS00420; SRCR_1; 1.
DR PROSITE; PS50287; SRCR_2; 4.
PE 2: Evidence at transcript level;
KW Basement membrane; Calcium; Chromatin regulator; Chromosome; Copper;
KW Disulfide bond; Endoplasmic reticulum; Extracellular matrix; Glycoprotein;
KW LTQ; Metal-binding; Nucleus; Oxidoreductase; Reference proteome; Repeat;
KW Repressor; Secreted; Signal; TPQ; Transcription; Transcription regulation.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..737
FT /note="Lysyl oxidase homolog 2A"
FT /id="PRO_0000418004"
FT DOMAIN 29..130
FT /note="SRCR 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DOMAIN 159..270
FT /note="SRCR 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DOMAIN 294..393
FT /note="SRCR 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DOMAIN 403..512
FT /note="SRCR 4"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT REGION 516..718
FT /note="Lysyl-oxidase like"
FT /evidence="ECO:0000250"
FT BINDING 517
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT BINDING 518
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT BINDING 593
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT BINDING 595
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT BINDING 597
FT /ligand="Cu cation"
FT /ligand_id="ChEBI:CHEBI:23378"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT BINDING 689
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT BINDING 691
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT BINDING 694
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT BINDING 695
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT MOD_RES 656
FT /note="2',4',5'-topaquinone"
FT /evidence="ECO:0000250|UniProtKB:P33072"
FT CARBOHYD 256
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 423
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 611
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 55..119
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 68..129
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 99..109
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 188..259
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 201..269
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 235..245
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 319..382
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 332..392
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 363..373
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 432..498
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 445..511
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 479..489
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT DISULFID 541..592
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT DISULFID 547..662
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT DISULFID 624..640
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT DISULFID 630..652
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K0"
FT DISULFID 699..713
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00196"
FT CROSSLNK 620..656
FT /note="Lysine tyrosylquinone (Lys-Tyr)"
FT /evidence="ECO:0000250|UniProtKB:P33072"
FT CONFLICT 9..11
FT /note="IFS -> VFG (in Ref. 1; ABM86967)"
FT /evidence="ECO:0000305"
FT CONFLICT 16
FT /note="A -> V (in Ref. 1; ABM86967)"
FT /evidence="ECO:0000305"
FT CONFLICT 147
FT /note="V -> I (in Ref. 1; ABM86967)"
FT /evidence="ECO:0000305"
FT CONFLICT 181
FT /note="R -> W (in Ref. 1; ABM86967)"
FT /evidence="ECO:0000305"
FT CONFLICT 200
FT /note="A -> V (in Ref. 1; ABM86967)"
FT /evidence="ECO:0000305"
FT CONFLICT 232
FT /note="S -> L (in Ref. 1; ABM86967)"
FT /evidence="ECO:0000305"
FT CONFLICT 242
FT /note="V -> M (in Ref. 1; ABM86967)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 737 AA; 82334 MW; CBB61E1520E97ED3 CRC64;
MAVSSALCIF SLLVLAQAQS ELQQPKIELR LAGDKRKHYE GRLEVFYNNE WGTVCDDDFS
IEAAHVACRQ LGFLGAVAWS PSAKFGQGEG RIWLDNVHCT GRENSLAACP SNGFGVSDCR
HSEDVGVICN QKRIPGHRFI NIMNNNVETL EERVEEIRIR PISSHLKRIP ITEGYVEVKE
RGKWRQICDE EWTPLNSRVA CGMYGFPGEK NYNNKVYRSL SMRKKKNYWG FSVNCTGNEA
HVSSCRLGKA LEPKRNGTCG RGLPVVVSCV PGRAFAPSSS IGFRKAYRPE QPLVRLRGGA
NVGEGRVEVL KNGVWGTVCD DNWNLKAATV VCRELGFGSA KEALTGAKLG QGMGPVHMNE
VECSGFEKSL TDCYFNNDAL GCSHEEDAAV RCNVPAMGFQ KRIRLSGGRN PFEGRVEVLA
EKNGSLVWGT VCSENWGIIE AMVVCRQLGL GFASHAFQET WYWAGDANAD NVVMSGVRCS
GTEMSLPQCL HHGKHINCPK GGGRFAAGVS CSDTAPDLVL NAQLVEQTTY LEDRPMYALQ
CALEENCLSS TARKNDHSSY RRLLRFSSQI HNVGQSDFRP KLGYHAWTWH ECHRHYHSME
VFTHYDLLSL NGTKVAEGHK ASFCLEDTHC DEGISKRYHC ANFGEQGITV GCWDTYRHDI
DCQWIDVTDV KPGDYIFQVV INPNYDVAES DYTNNVMKCK CRYDGYRIWT YSCHIGGSRS
SDMDEYSGMS NQLNHLR
