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Protein

Lysyl oxidase homolog 2

Gene

LOXL2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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). When secreted in extracellular matrix, promotes cross-linking of extracellular matrix proteins by mediating oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin. Acts as a regulator of sprouting angiogenesis, probably via collagen IV scaffolding. When nuclear, acts as a transcription corepressor and specifically mediates deamination of trimethylated 'Lys-4' of histone H3 (H3K4me3), a specific tag for epigenetic transcriptional activation. Involved in epithelial to mesenchymal transition (EMT) via interaction with SNAI1 and participates in repression of E-cadherin, probably by mediating deamination of histone H3. Also involved in E-cadherin repression following hypoxia, a hallmark of epithelial to mesenchymal transition believed to amplify tumor aggressiveness, suggesting that it may play a role in tumor progression. Acts as a regulator of chondrocyte differentiation, probably by regulating expression of factors that control chondrocyte differentiation.6 Publications

Miscellaneous

Its overexpression in a number of cancer 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:21732535). Allosteric inhibition by AB0023 inhibits formation of the tumor microenvironment and reduces metastatic tumor burden in xenograft models (PubMed:20818376 and PubMed:21732535). However, inhibiting the enzyme activity of LOXL2 may not be sufficient, since mutants that lack enzyme activity or inhibition of the activity by AB0023 antibody does not prevent inhibition of the differentiation of keratinocytes, thereby promoting development of squamous cell carcinomas (PubMed:22157764).2 Publications

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

    • chromatin binding Source: UniProtKB
    • copper ion binding Source: InterPro
    • electron carrier activity Source: UniProtKB
    • methylated histone binding Source: UniProtKB
    • oligosaccharide binding Source: UniProtKB
    • protein-lysine 6-oxidase activity Source: UniProtKB
    • scavenger receptor activity Source: InterPro
    • transcription corepressor activity Source: UniProtKB

    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
    • histone modification Source: UniProtKB
    • negative regulation of transcription, DNA-templated Source: UniProtKB
    • oxidation-reduction process Source: UniProtKB
    • positive regulation of chondrocyte differentiation Source: UniProtKB
    • protein deamination 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.

    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

    HGNCiHGNC:6666. LOXL2.

    Subcellular locationi

    GO - Cellular componenti

    • basement membrane Source: UniProtKB
    • chromosome Source: UniProtKB-SubCell
    • extracellular matrix Source: BHF-UCL
    • extracellular space Source: UniProtKB
    • membrane Source: InterPro
    • nucleoplasm Source: HPA
    • nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Basement membrane, Chromosome, Extracellular matrix, Nucleus, Secreted

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi455N → Q: Inhibits secretion. 1 Publication1
    Mutagenesisi626 – 628HRH → ARA: Loss of catalytic activity and abolishes ability to repress transcription. 1 Publication3
    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

    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...)Sequence analysis1
    Disulfide bondi351 ↔ 414PROSITE-ProRule annotation
    Disulfide bondi364 ↔ 424PROSITE-ProRule annotation
    Disulfide bondi395 ↔ 405PROSITE-ProRule annotation
    Glycosylationi455N-linked (GlcNAc...) (complex)1 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)1 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. Highest expression in reproductive tissues, placenta, uterus and prostate. Up-regulated in a number of cancers cells and tissues.

    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 SNAI1.1 Publication

    Binary interactionsi

    Show more details

    GO - Molecular functioni

    • methylated histone binding Source: UniProtKB

    Protein-protein interaction databases

    BioGridi110201. 30 interactors.
    IntActiQ9Y4K0. 12 interactors.
    MINTiMINT-4053647.
    STRINGi9606.ENSP00000373783.

    Structurei

    3D structure databases

    ProteinModelPortaliQ9Y4K0.
    SMRiQ9Y4K0.
    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.
    GeneTreeiENSGT00870000136394.
    HOGENOMiHOG000220841.
    HOVERGENiHBG052336.
    InParanoidiQ9Y4K0.
    KOiK00280.
    OMAiHVVCGMF.
    OrthoDBiEOG091G02XD.
    PhylomeDBiQ9Y4K0.
    TreeFamiTF326061.

    Family and domain databases

    Gene3Di3.10.250.10. 2 hits.
    InterProiView protein in InterPro
    IPR001695. Lysyl_oxidase.
    IPR019828. Lysyl_oxidase_CS.
    IPR001190. SRCR.
    IPR017448. SRCR-like_dom.
    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_050009308S → R. Corresponds to variant dbSNP:rs4871866Ensembl.1
    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

    Cross-referencesi

    Web resourcesi

    Atlas of Genetics and Cytogenetics in Oncology and Haematology

    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.

    3D structure databases

    ProteinModelPortaliQ9Y4K0.
    SMRiQ9Y4K0.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi110201. 30 interactors.
    IntActiQ9Y4K0. 12 interactors.
    MINTiMINT-4053647.
    STRINGi9606.ENSP00000373783.

    Chemistry databases

    GuidetoPHARMACOLOGYi2853.

    PTM databases

    iPTMnetiQ9Y4K0.
    PhosphoSitePlusiQ9Y4K0.

    Polymorphism and mutation databases

    BioMutaiLOXL2.
    DMDMi13878585.

    Proteomic databases

    EPDiQ9Y4K0.
    MaxQBiQ9Y4K0.
    PaxDbiQ9Y4K0.
    PeptideAtlasiQ9Y4K0.
    PRIDEiQ9Y4K0.

    Protocols and materials databases

    DNASUi4017.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

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

    Organism-specific databases

    CTDi4017.
    DisGeNETi4017.
    GeneCardsiLOXL2.
    H-InvDBiHIX0007387.
    HGNCiHGNC:6666. LOXL2.
    HPAiCAB025848.
    HPA036257.
    HPA056542.
    MIMi606663. gene.
    neXtProtiNX_Q9Y4K0.
    OpenTargetsiENSG00000134013.
    PharmGKBiPA30429.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiENOG410IE2X. Eukaryota.
    ENOG410XSN1. LUCA.
    GeneTreeiENSGT00870000136394.
    HOGENOMiHOG000220841.
    HOVERGENiHBG052336.
    InParanoidiQ9Y4K0.
    KOiK00280.
    OMAiHVVCGMF.
    OrthoDBiEOG091G02XD.
    PhylomeDBiQ9Y4K0.
    TreeFamiTF326061.

    Enzyme and pathway databases

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

    Miscellaneous databases

    ChiTaRSiLOXL2. human.
    GeneWikiiLOXL2.
    GenomeRNAii4017.
    PROiPR:Q9Y4K0.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000134013.
    CleanExiHS_LOXL2.
    ExpressionAtlasiQ9Y4K0. baseline and differential.
    GenevisibleiQ9Y4K0. HS.

    Family and domain databases

    Gene3Di3.10.250.10. 2 hits.
    InterProiView protein in InterPro
    IPR001695. Lysyl_oxidase.
    IPR019828. Lysyl_oxidase_CS.
    IPR001190. SRCR.
    IPR017448. SRCR-like_dom.
    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.
    ProtoNetiSearch...

    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: April 12, 2017
    This is version 156 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

    Complete proteome, Reference proteome

    Documents

    1. Human chromosome 8
      Human chromosome 8: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.