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Protein

Lysyl oxidase homolog 2

Gene

LOXL2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Mediates the post-translational oxidative deamination of lysine residues on target proteins leading to the formation of deaminated lysine (allysine) (PubMed:27735137). Acts as a transcription corepressor and specifically mediates deamination of trimethylated 'Lys-4' of histone H3 (H3K4me3), a specific tag for epigenetic transcriptional activation (PubMed:27735137). Shows no activity against histone H3 when it is trimethylated on 'Lys-9' (H3K9me3) or 'Lys-27' (H3K27me3) or when 'Lys-4' is monomethylated (H3K4me1) or dimethylated (H3K4me2) (PubMed:27735137). Also mediates deamination of methylated TAF10, a member of the transcription factor IID (TFIID) complex, which induces release of TAF10 from promoters, leading to inhibition of TFIID-dependent transcription (PubMed:25959397). LOXL2-mediated deamination of TAF10 results in transcriptional repression of genes required for embryonic stem cell pluripotency including POU5F1/OCT4, NANOG, KLF4 and SOX2 (By similarity). Involved in epithelial to mesenchymal transition (EMT) via interaction with SNAI1 and participates in repression of E-cadherin CDH1, probably by mediating deamination of histone H3 (PubMed:16096638, PubMed:27735137, PubMed:24414204). During EMT, involved with SNAI1 in negatively regulating pericentromeric heterochromatin transcription (PubMed:24239292). SNAI1 recruits LOXL2 to pericentromeric regions to oxidize histone H3 and repress transcription which leads to release of heterochromatin component CBX5/HP1A, enabling chromatin reorganization and acquisition of mesenchymal traits (PubMed:24239292). Interacts with the endoplasmic reticulum protein HSPA5 which activates the IRE1-XBP1 pathway of the unfolded protein response, leading to expression of several transcription factors involved in EMT and subsequent EMT induction (PubMed:28332555). Involved in E-cadherin repression following hypoxia, a hallmark of EMT believed to amplify tumor aggressiveness, suggesting that it may play a role in tumor progression (PubMed:20026874). When secreted into the extracellular matrix, promotes cross-linking of extracellular matrix proteins by mediating oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin (PubMed:20306300). Acts as a regulator of sprouting angiogenesis, probably via collagen IV scaffolding (PubMed:21835952). Acts as a regulator of chondrocyte differentiation, probably by regulating expression of factors that control chondrocyte differentiation (By similarity).By similarity8 Publications

Miscellaneous

Its overexpression in a number of cancers and its ability to promote epithelial to mesenchymal transition suggest that LOXL2 might play a role in tumor progression: expression is correlated with metastasis and decreased survival in patients with aggressive breast cancer (PubMed:21233336, PubMed:21732535). Allosteric inhibition by AB0023 inhibits formation of the tumor microenvironment and reduces metastatic tumor burden in xenograft models (PubMed:20818376, PubMed:21732535). However, inhibiting the enzyme activity of LOXL2 may not be sufficient, since inhibition of keratinocyte differentiation is not prevented in mutants that lack enzyme activity nor by inhibition of activity by the AB0023 antibody, thereby promoting development of squamous cell carcinomas (PubMed:22157764).4 Publications

Caution

The original paper reporting the role of LOXL2 in deamination of trimethylated 'Lys-4' of histone H3 was retracted due to inappropriate manipulation of figure data (PubMed:22483618, PubMed:27392148). However, this role was confirmed in a subsequent publication (PubMed:27735137).2 Publications1 Publication

Catalytic activityi

[Protein]-L-lysine + O2 + H2O = [protein]-(S)-2-amino-6-oxohexanoate + NH3 + H2O2.3 Publications

Cofactori

Protein has several cofactor binding sites:
  • Cu cationBy similarity
  • lysine tyrosylquinone residueBy similarityNote: Contains 1 lysine tyrosylquinone.By similarity

Enzyme regulationi

According to some reports, it is inhibited by beta-aminopropionitrile (BAPN) (PubMed:20439985 and PubMed:23319596). According to another report, it is not inhibited by beta-aminopropionitrile (BAPN) (PubMed:20306300). Specifically inhibited by a mouse monoclonal antibody AB0023, inhibition occurs in a non-competitive manner.4 Publications

Kineticsi

kcat is 2.04 min(-1) with tropoelastin as substrate (without the first three SRCR domains). kcat is 0.62 min(-1) with tropoelastin as substrate (without all four SRCR domains).
  1. KM=1.01 mM for 1,5-diaminopentane2 Publications
  2. KM=1.05 mM for spermine2 Publications
  3. KM=0.59 µM for tropoelastin (without the first three SRCR domains)2 Publications
  4. KM=0.62 µM for tropoelastin (without all four SRCR domains)2 Publications

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi626CopperSequence analysis1
    Metal bindingi628CopperSequence analysis1
    Metal bindingi630CopperSequence analysis1

    GO - Molecular functioni

    • copper ion binding Source: InterPro
    • electron transfer activity Source: UniProtKB
    • oligosaccharide binding Source: UniProtKB
    • protein-lysine 6-oxidase activity Source: UniProtKB
    • scavenger receptor activity Source: InterPro

    GO - Biological processi

    • aging Source: ProtInc
    • cell adhesion Source: ProtInc
    • cellular protein modification process Source: UniProtKB
    • collagen fibril organization Source: UniProtKB
    • endothelial cell migration Source: UniProtKB
    • endothelial cell proliferation Source: UniProtKB
    • epithelial to mesenchymal transition Source: UniProtKB
    • heterochromatin organization Source: UniProtKB
    • negative regulation of stem cell population maintenance Source: UniProtKB
    • negative regulation of transcription, DNA-templated Source: UniProtKB
    • negative regulation of transcription by RNA polymerase II Source: UniProtKB
    • peptidyl-lysine oxidation Source: UniProtKB
    • positive regulation of chondrocyte differentiation Source: UniProtKB
    • positive regulation of epithelial to mesenchymal transition Source: UniProtKB
    • response to copper ion Source: UniProtKB
    • response to hypoxia Source: UniProtKB
    • sprouting angiogenesis Source: UniProtKB
    • transcription, DNA-templated Source: UniProtKB-KW

    Keywordsi

    Molecular functionChromatin regulator, Oxidoreductase, Repressor
    Biological processTranscription, Transcription regulation
    LigandCopper, Metal-binding

    Enzyme and pathway databases

    BRENDAi1.4.3.13 2681
    ReactomeiR-HSA-1566948 Elastic fibre formation
    R-HSA-2243919 Crosslinking of collagen fibrils
    SIGNORiQ9Y4K0

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Lysyl oxidase homolog 2 (EC:1.4.3.133 Publications)
    Alternative name(s):
    Lysyl oxidase-like protein 2
    Lysyl oxidase-related protein 2
    Lysyl oxidase-related protein WS9-14
    Gene namesi
    Name:LOXL2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 8

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000134013.15
    HGNCiHGNC:6666 LOXL2
    MIMi606663 gene
    neXtProtiNX_Q9Y4K0

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Basement membrane, Chromosome, Endoplasmic reticulum, Extracellular matrix, Nucleus, Secreted

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi455N → Q: Inhibits secretion. 1 Publication1
    Mutagenesisi626 – 628HRH → ARA: Abolishes oxidase activity and oxidation of trimethylated 'Lys-4' of histone H3 but does not affect secretion, interaction with SNAI1, binding to the CDH1 promoter, repression of CDH1 transcription or ability to induce EMT. 2 Publications3
    Mutagenesisi644N → Q: Inhibits secretion. 1 Publication1
    Mutagenesisi689Y → F: Does not affect ability to inhibit keratinocyte differentiation. 1 Publication1

    Organism-specific databases

    DisGeNETi4017
    OpenTargetsiENSG00000134013
    PharmGKBiPA30429

    Chemistry databases

    ChEMBLiCHEMBL3714029
    GuidetoPHARMACOLOGYi2853

    Polymorphism and mutation databases

    BioMutaiLOXL2
    DMDMi13878585

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Signal peptidei1 – 25Sequence analysisAdd BLAST25
    ChainiPRO_000001853226 – 774Lysyl oxidase homolog 2Add BLAST749

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Disulfide bondi84 ↔ 148PROSITE-ProRule annotation
    Disulfide bondi97 ↔ 158PROSITE-ProRule annotation
    Disulfide bondi128 ↔ 138PROSITE-ProRule annotation
    Disulfide bondi218 ↔ 291PROSITE-ProRule annotation
    Disulfide bondi231 ↔ 301PROSITE-ProRule annotation
    Disulfide bondi265 ↔ 275PROSITE-ProRule annotation
    Glycosylationi288N-linked (GlcNAc...) asparagineSequence analysis1
    Disulfide bondi351 ↔ 414PROSITE-ProRule annotation
    Disulfide bondi364 ↔ 424PROSITE-ProRule annotation
    Disulfide bondi395 ↔ 405PROSITE-ProRule annotation
    Glycosylationi455N-linked (GlcNAc...) (complex) asparagine1 Publication1
    Disulfide bondi464 ↔ 530PROSITE-ProRule annotation
    Disulfide bondi477 ↔ 543PROSITE-ProRule annotation
    Disulfide bondi511 ↔ 521PROSITE-ProRule annotation
    Disulfide bondi573 ↔ 579PROSITE-ProRule annotation
    Disulfide bondi625 ↔ 673PROSITE-ProRule annotation
    Glycosylationi644N-linked (GlcNAc...) (complex) asparagine1 Publication1
    Cross-linki653 ↔ 689Lysine tyrosylquinone (Lys-Tyr)1 Publication
    Disulfide bondi657 ↔ 663PROSITE-ProRule annotation
    Disulfide bondi685 ↔ 695PROSITE-ProRule annotation
    Modified residuei6892',4',5'-topaquinoneBy similarity1
    Disulfide bondi732 ↔ 746PROSITE-ProRule annotation

    Post-translational modificationi

    The lysine tyrosylquinone cross-link (LTQ) is generated by condensation of the epsilon-amino group of a lysine with a topaquinone produced by oxidation of tyrosine.1 Publication
    N-glycosylated. N-glycosylation on Asn-455 and Asn-644 may be essential for proper folding and secretion; may be composed of a fucosylated carbohydrates attached to a trimannose N-linked glycan core.1 Publication

    Keywords - PTMi

    Disulfide bond, Glycoprotein, LTQ, TPQ

    Proteomic databases

    EPDiQ9Y4K0
    MaxQBiQ9Y4K0
    PaxDbiQ9Y4K0
    PeptideAtlasiQ9Y4K0
    PRIDEiQ9Y4K0

    PTM databases

    iPTMnetiQ9Y4K0
    PhosphoSitePlusiQ9Y4K0

    Expressioni

    Tissue specificityi

    Expressed in many tissues (PubMed:10212285). Highest expression in reproductive tissues, placenta, uterus and prostate (PubMed:10212285). In esophageal epithelium, expressed in the basal, prickle and granular cell layers (PubMed:22204712). Up-regulated in a number of cancers cells and tissues.2 Publications

    Inductioni

    Strongly induced in hypoxia. Direct transcriptional target of HIF1A.1 Publication

    Gene expression databases

    BgeeiENSG00000134013
    CleanExiHS_LOXL2
    ExpressionAtlasiQ9Y4K0 baseline and differential
    GenevisibleiQ9Y4K0 HS

    Organism-specific databases

    HPAiCAB025848
    HPA036257
    HPA056542

    Interactioni

    Subunit structurei

    Component of some chromatin repressor complex. Interacts with SNAI1 (PubMed:16096638). Interacts with TAF10 (PubMed:25959397). Interacts with HSPA5 (PubMed:28332555).3 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    MARCKSL1P490064EBI-7172227,EBI-4289961

    Protein-protein interaction databases

    BioGridi110201, 43 interactors
    IntActiQ9Y4K0, 3 interactors
    MINTiQ9Y4K0
    STRINGi9606.ENSP00000373783

    Structurei

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5ZE3X-ray2.40A/B318-774[»]
    ProteinModelPortaliQ9Y4K0
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini58 – 159SRCR 1PROSITE-ProRule annotationAdd BLAST102
    Domaini188 – 302SRCR 2PROSITE-ProRule annotationAdd BLAST115
    Domaini326 – 425SRCR 3PROSITE-ProRule annotationAdd BLAST100
    Domaini435 – 544SRCR 4PROSITE-ProRule annotationAdd BLAST110

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni548 – 751Lysyl-oxidase likeAdd BLAST204

    Domaini

    The fourth SRCR domain plays a important role in optimizing the catalytic activity of the lysyl-oxidase like (LOX) catalytic domain.

    Sequence similaritiesi

    Belongs to the lysyl oxidase family.Curated

    Keywords - Domaini

    Repeat, Signal

    Phylogenomic databases

    eggNOGiENOG410IE2X Eukaryota
    ENOG410XSN1 LUCA
    GeneTreeiENSGT00900000140830
    HOGENOMiHOG000220841
    HOVERGENiHBG052336
    InParanoidiQ9Y4K0
    KOiK00280
    OMAiFSMDCTG
    OrthoDBiEOG091G02XD
    PhylomeDBiQ9Y4K0
    TreeFamiTF326061

    Family and domain databases

    Gene3Di3.10.250.10, 4 hits
    InterProiView protein in InterPro
    IPR001695 Lysyl_oxidase
    IPR019828 Lysyl_oxidase_CS
    IPR001190 SRCR
    IPR017448 SRCR-like_dom
    IPR036772 SRCR-like_dom_sf
    PfamiView protein in Pfam
    PF01186 Lysyl_oxidase, 1 hit
    PF00530 SRCR, 4 hits
    PRINTSiPR00074 LYSYLOXIDASE
    PR00258 SPERACTRCPTR
    SMARTiView protein in SMART
    SM00202 SR, 4 hits
    SUPFAMiSSF56487 SSF56487, 4 hits
    PROSITEiView protein in PROSITE
    PS00926 LYSYL_OXIDASE, 1 hit
    PS00420 SRCR_1, 2 hits
    PS50287 SRCR_2, 4 hits

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    Q9Y4K0-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MERPLCSHLC SCLAMLALLS PLSLAQYDSW PHYPEYFQQP APEYHQPQAP
    60 70 80 90 100
    ANVAKIQLRL AGQKRKHSEG RVEVYYDGQW GTVCDDDFSI HAAHVVCREL
    110 120 130 140 150
    GYVEAKSWTA SSSYGKGEGP IWLDNLHCTG NEATLAACTS NGWGVTDCKH
    160 170 180 190 200
    TEDVGVVCSD KRIPGFKFDN SLINQIENLN IQVEDIRIRA ILSTYRKRTP
    210 220 230 240 250
    VMEGYVEVKE GKTWKQICDK HWTAKNSRVV CGMFGFPGER TYNTKVYKMF
    260 270 280 290 300
    ASRRKQRYWP FSMDCTGTEA HISSCKLGPQ VSLDPMKNVT CENGLPAVVS
    310 320 330 340 350
    CVPGQVFSPD GPSRFRKAYK PEQPLVRLRG GAYIGEGRVE VLKNGEWGTV
    360 370 380 390 400
    CDDKWDLVSA SVVCRELGFG SAKEAVTGSR LGQGIGPIHL NEIQCTGNEK
    410 420 430 440 450
    SIIDCKFNAE SQGCNHEEDA GVRCNTPAMG LQKKLRLNGG RNPYEGRVEV
    460 470 480 490 500
    LVERNGSLVW GMVCGQNWGI VEAMVVCRQL GLGFASNAFQ ETWYWHGDVN
    510 520 530 540 550
    SNKVVMSGVK CSGTELSLAH CRHDGEDVAC PQGGVQYGAG VACSETAPDL
    560 570 580 590 600
    VLNAEMVQQT TYLEDRPMFM LQCAMEENCL SASAAQTDPT TGYRRLLRFS
    610 620 630 640 650
    SQIHNNGQSD FRPKNGRHAW IWHDCHRHYH SMEVFTHYDL LNLNGTKVAE
    660 670 680 690 700
    GHKASFCLED TECEGDIQKN YECANFGDQG ITMGCWDMYR HDIDCQWVDI
    710 720 730 740 750
    TDVPPGDYLF QVVINPNFEV AESDYSNNIM KCRSRYDGHR IWMYNCHIGG
    760 770
    SFSEETEKKF EHFSGLLNNQ LSPQ
    Length:774
    Mass (Da):86,725
    Last modified:November 1, 1999 - v1
    Checksum:i9DF5D25D4824BCCD
    GO

    Sequence cautioni

    The sequence AAD34343 differs from that shown. Reason: Erroneous termination at position 775. Translated as stop.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti184E → K in BAG35197 (PubMed:14702039).Curated1
    Sequence conflicti239E → G in BAD96197 (Ref. 3) Curated1
    Sequence conflicti295L → Q in AAD34343 (PubMed:10212285).Curated1
    Sequence conflicti536Q → R in BAG35197 (PubMed:14702039).Curated1
    Sequence conflicti652H → Q in AAD34343 (PubMed:10212285).Curated1
    Sequence conflicti746C → S in AAD34343 (PubMed:10212285).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_050010359S → W. Corresponds to variant dbSNP:rs4602894Ensembl.1
    Natural variantiVAR_024527570M → L2 PublicationsCorresponds to variant dbSNP:rs1063582Ensembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    U89942 mRNA Translation: AAB49697.1
    AK312266 mRNA Translation: BAG35197.1
    AK222477 mRNA Translation: BAD96197.1
    AC090197 Genomic DNA No translation available.
    BC000594 mRNA Translation: AAH00594.1
    AF117949 mRNA Translation: AAD34343.1 Sequence problems.
    CCDSiCCDS34864.1
    RefSeqiNP_002309.1, NM_002318.2
    UniGeneiHs.626637

    Genome annotation databases

    EnsembliENST00000389131; ENSP00000373783; ENSG00000134013
    GeneIDi4017
    KEGGihsa:4017
    UCSCiuc003xdh.2 human

    Keywords - Coding sequence diversityi

    Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiLOXL2_HUMAN
    AccessioniPrimary (citable) accession number: Q9Y4K0
    Secondary accession number(s): B2R5Q0
    , Q53HV3, Q9BW70, Q9Y5Y8
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 27, 2001
    Last sequence update: November 1, 1999
    Last modified: May 23, 2018
    This is version 168 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

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