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Protein

Kallikrein-6

Gene

KLK6

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

Functioni

Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.6 Publications

Enzyme regulationi

Inhibited by a range of serine protease inhibitors including soybean trypsin inhibitor, benzamidine and serpins. Activated by a range of glycosaminoglycans including chondroitin sulfate, dermatan sulfate, heparan sulfate and heparin.2 Publications

Kineticsi

  1. KM=1562 µM for Tosyl-Gly-Pro-Arg-AMC2 Publications
  2. KM=777 µM for Tosyl-Gly-Pro-Lys-AMC2 Publications
  3. KM=0.410 mM for Phe-Ser-Arg-AMC2 Publications
  4. KM=0.455 mM for Gly-Gly-Arg-AMC2 Publications
  5. KM=0.335 mM for Asp-Pro-Arg-AMC2 Publications
  6. KM=0.758 mM for Gln-Gly-Arg-AMC2 Publications
  7. KM=0.625 mM for Pro-Phe-Arg-AMC2 Publications
  8. KM=0.271 mM for Val-Pro-Arg-AMC2 Publications
  9. KM=1.72 mM for Val-Leu-Lys-AMC2 Publications

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei62Charge relay system1 Publication1
    Active sitei106Charge relay system1 Publication1
    Active sitei197Charge relay system1 Publication1

    GO - Molecular functioni

    • serine-type endopeptidase activity Source: UniProtKB

    GO - Biological processi

    • amyloid precursor protein metabolic process Source: UniProtKB
    • central nervous system development Source: UniProtKB
    • collagen catabolic process Source: UniProtKB
    • hormone metabolic process Source: UniProtKB
    • myelination Source: UniProtKB
    • neuron death Source: UniProtKB
    • positive regulation of G-protein coupled receptor protein signaling pathway Source: UniProtKB
    • protein autoprocessing Source: UniProtKB
    • regulation of cell differentiation Source: UniProtKB
    • regulation of neuron projection development Source: Ensembl
    • response to wounding Source: UniProtKB
    • tissue regeneration Source: UniProtKB

    Keywordsi

    Molecular functionHydrolase, Protease, Serine protease

    Enzyme and pathway databases

    BRENDAi3.4.21.104 2681
    3.4.21.34 2681
    3.4.21.B10 2681
    SABIO-RKiQ92876

    Protein family/group databases

    MEROPSiS01.236

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Kallikrein-6 (EC:3.4.21.-)
    Alternative name(s):
    Neurosin
    Protease M
    SP59
    Serine protease 18
    Serine protease 9
    Zyme
    Gene namesi
    Name:KLK6
    Synonyms:PRSS18, PRSS9
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 19

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000167755.13
    HGNCiHGNC:6367 KLK6
    MIMi602652 gene
    neXtProtiNX_Q92876

    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

    Cytoplasm, Endoplasmic reticulum, Microsome, Mitochondrion, Nucleus, Secreted

    Pathology & Biotechi

    Organism-specific databases

    DisGeNETi5653
    OpenTargetsiENSG00000167755
    PharmGKBiPA30156

    Chemistry databases

    ChEMBLiCHEMBL4448
    DrugBankiDB03127 Benzamidine
    GuidetoPHARMACOLOGYi2376

    Polymorphism and mutation databases

    BioMutaiKLK6
    DMDMi3914480

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Signal peptidei1 – 16Sequence analysisAdd BLAST16
    PropeptideiPRO_000002794017 – 21Activation peptideSequence analysis5
    ChainiPRO_000002794122 – 244Kallikrein-6Add BLAST223

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Disulfide bondi28 ↔ 157
    Disulfide bondi47 ↔ 63
    Disulfide bondi131 ↔ 231
    Glycosylationi134N-linked (GlcNAc...) asparagineSequence analysis1
    Disulfide bondi138 ↔ 203
    Disulfide bondi168 ↔ 182
    Disulfide bondi193 ↔ 218

    Post-translational modificationi

    Inactivated by autolytic cleavage after Arg-80.

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sitei80 – 81Cleavage; by autolysis2

    Keywords - PTMi

    Autocatalytic cleavage, Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Zymogen

    Proteomic databases

    EPDiQ92876
    MaxQBiQ92876
    PaxDbiQ92876
    PeptideAtlasiQ92876
    PRIDEiQ92876
    ProteomicsDBi75559
    75560 [Q92876-2]
    75561 [Q92876-3]

    PTM databases

    PhosphoSitePlusiQ92876
    UniCarbKBiQ92876

    Miscellaneous databases

    PMAP-CutDBiQ92876

    Expressioni

    Tissue specificityi

    In fluids, highest levels found in milk of lactating women followed by cerebrospinal fluid, nipple aspirate fluid and breast cyst fluid. Also found in serum, seminal plasma and some amniotic fluids and breast tumor cytosolic extracts. Not detected in urine. At the tissue level, highest concentrations found in glandular tissues such as salivary glands followed by lung, colon, fallopian tube, placenta, breast, pituitary and kidney. Not detected in skin, spleen, bone, thyroid, heart, ureter, liver, muscle, endometrium, testis, pancreas, seminal vesicle, ovary, adrenals and prostate. In brain, detected in gray matter neurons (at protein level). Colocalizes with pathological inclusions such as Lewy bodies and glial cytoplasmic inclusions. Overexpressed in primary breast tumors but not expressed in metastatic tumors.5 Publications

    Inductioni

    By spinal cord injury. This effect is particularly prominent in macrophages, microglia and reactive astrocytes.1 Publication

    Gene expression databases

    BgeeiENSG00000167755
    CleanExiHS_KLK6
    ExpressionAtlasiQ92876 baseline and differential
    GenevisibleiQ92876 HS

    Organism-specific databases

    HPAiHPA051837

    Interactioni

    Protein-protein interaction databases

    BioGridi111634, 12 interactors
    IntActiQ92876, 16 interactors
    MINTiQ92876
    STRINGi9606.ENSP00000309148

    Chemistry databases

    BindingDBiQ92876

    Structurei

    Secondary structure

    1244
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi27 – 29Combined sources3
    Beta strandi36 – 41Combined sources6
    Beta strandi44 – 53Combined sources10
    Beta strandi56 – 59Combined sources4
    Helixi61 – 63Combined sources3
    Beta strandi69 – 73Combined sources5
    Beta strandi75 – 77Combined sources3
    Beta strandi85 – 94Combined sources10
    Turni100 – 102Combined sources3
    Beta strandi108 – 114Combined sources7
    Beta strandi137 – 144Combined sources8
    Beta strandi146 – 149Combined sources4
    Beta strandi156 – 163Combined sources8
    Helixi165 – 171Combined sources7
    Turni173 – 175Combined sources3
    Beta strandi180 – 184Combined sources5
    Turni186 – 188Combined sources3
    Turni194 – 198Combined sources5
    Beta strandi200 – 203Combined sources4
    Beta strandi206 – 213Combined sources8
    Beta strandi221 – 223Combined sources3
    Beta strandi225 – 229Combined sources5
    Helixi230 – 233Combined sources4
    Helixi234 – 241Combined sources8

    3D structure databases

    ProteinModelPortaliQ92876
    SMRiQ92876
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ92876

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini22 – 242Peptidase S1PROSITE-ProRule annotationAdd BLAST221

    Sequence similaritiesi

    Belongs to the peptidase S1 family. Kallikrein subfamily.PROSITE-ProRule annotation

    Keywords - Domaini

    Signal

    Phylogenomic databases

    eggNOGiKOG3627 Eukaryota
    COG5640 LUCA
    GeneTreeiENSGT00760000118862
    HOGENOMiHOG000251820
    HOVERGENiHBG013304
    InParanoidiQ92876
    KOiK08667
    OMAiAWAEEQN
    OrthoDBiEOG091G0G5F
    PhylomeDBiQ92876
    TreeFamiTF331065

    Family and domain databases

    CDDicd00190 Tryp_SPc, 1 hit
    InterProiView protein in InterPro
    IPR009003 Peptidase_S1_PA
    IPR001314 Peptidase_S1A
    IPR001254 Trypsin_dom
    IPR018114 TRYPSIN_HIS
    IPR033116 TRYPSIN_SER
    PfamiView protein in Pfam
    PF00089 Trypsin, 1 hit
    PRINTSiPR00722 CHYMOTRYPSIN
    SMARTiView protein in SMART
    SM00020 Tryp_SPc, 1 hit
    SUPFAMiSSF50494 SSF50494, 1 hit
    PROSITEiView protein in PROSITE
    PS50240 TRYPSIN_DOM, 1 hit
    PS00134 TRYPSIN_HIS, 1 hit
    PS00135 TRYPSIN_SER, 1 hit

    Sequences (3)i

    Sequence statusi: Complete.

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

    This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: Q92876-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MKKLMVVLSL IAAAWAEEQN KLVHGGPCDK TSHPYQAALY TSGHLLCGGV
    60 70 80 90 100
    LIHPLWVLTA AHCKKPNLQV FLGKHNLRQR ESSQEQSSVV RAVIHPDYDA
    110 120 130 140 150
    ASHDQDIMLL RLARPAKLSE LIQPLPLERD CSANTTSCHI LGWGKTADGD
    160 170 180 190 200
    FPDTIQCAYI HLVSREECEH AYPGQITQNM LCAGDEKYGK DSCQGDSGGP
    210 220 230 240
    LVCGDHLRGL VSWGNIPCGS KEKPGVYTNV CRYTNWIQKT IQAK
    Length:244
    Mass (Da):26,856
    Last modified:February 1, 1997 - v1
    Checksum:iAEA03F9145D87AAB
    GO
    Isoform 2 (identifier: Q92876-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-107: Missing.

    Show »
    Length:137
    Mass (Da):15,055
    Checksum:i25A421C212869BEA
    GO
    Isoform 3 (identifier: Q92876-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         14-40: AWAEEQNKLVHGGPCDKTSHPYQAALY → GIFRSSWGSITFGKGRVPRSRVLLSGL
         41-244: Missing.

    Show »
    Length:40
    Mass (Da):4,333
    Checksum:i323721E6AE557378
    GO

    Mass spectrometryi

    Molecular mass is 25866 Da from positions 22 - 244. Determined by MALDI. 1 Publication

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_06177678R → W. Corresponds to variant dbSNP:rs61469141Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0344031 – 107Missing in isoform 2. 1 PublicationAdd BLAST107
    Alternative sequenceiVSP_03440414 – 40AWAEE…QAALY → GIFRSSWGSITFGKGRVPRS RVLLSGL in isoform 3. 1 PublicationAdd BLAST27
    Alternative sequenceiVSP_03440541 – 244Missing in isoform 3. 1 PublicationAdd BLAST204

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    U62801 mRNA Translation: AAB07113.1
    D78203 mRNA Translation: BAA11306.1
    AF013988 mRNA Translation: AAB66483.1
    AF149289 Genomic DNA Translation: AAD51475.1
    AF243527 Genomic DNA Translation: AAG33359.1
    AY318867 mRNA Translation: AAP82446.1
    AY318868 mRNA No translation available.
    AY318869 mRNA Translation: AAP82448.1
    AY318870 mRNA No translation available.
    DQ223012 mRNA Translation: ABB04464.1
    AK314897 mRNA Translation: BAG37411.1
    BT006852 mRNA Translation: AAP35498.1
    AC011483 Genomic DNA No translation available.
    CH471135 Genomic DNA Translation: EAW71953.1
    CH471135 Genomic DNA Translation: EAW71954.1
    BC015525 mRNA Translation: AAH15525.1
    CCDSiCCDS12811.1 [Q92876-1]
    CCDS42599.1 [Q92876-2]
    RefSeqiNP_001012982.1, NM_001012964.2 [Q92876-1]
    NP_001012983.1, NM_001012965.2 [Q92876-2]
    NP_001306877.1, NM_001319948.1 [Q92876-2]
    NP_001306878.1, NM_001319949.1 [Q92876-2]
    NP_002765.1, NM_002774.3 [Q92876-1]
    UniGeneiHs.79361

    Genome annotation databases

    EnsembliENST00000310157; ENSP00000309148; ENSG00000167755 [Q92876-1]
    ENST00000376851; ENSP00000366047; ENSG00000167755 [Q92876-1]
    ENST00000391808; ENSP00000375684; ENSG00000167755 [Q92876-2]
    ENST00000594641; ENSP00000470482; ENSG00000167755 [Q92876-1]
    ENST00000597379; ENSP00000469630; ENSG00000167755 [Q92876-3]
    ENST00000599881; ENSP00000471948; ENSG00000167755 [Q92876-3]
    GeneIDi5653
    KEGGihsa:5653
    UCSCiuc002pui.4 human [Q92876-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiKLK6_HUMAN
    AccessioniPrimary (citable) accession number: Q92876
    Secondary accession number(s): A6NJA1, A8MW09, Q6H301
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 15, 1998
    Last sequence update: February 1, 1997
    Last modified: July 18, 2018
    This is version 163 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, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 19
      Human chromosome 19: 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. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Peptidase families
      Classification of peptidase families and list of entries
    7. SIMILARITY comments
      Index of protein domains and families

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