SPINK5
Srodni inhibitor limfo-epitelnog kazalskog tipa (LEKTI), poznat i kao inhibitor serinske proteaze Kazal-tip 5 (SPINK5) jest protein koji je kod ljudi kodiran genom SPINK5 sa hromosoma 5.[5][6]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 1.064 aminokiseline, а molekulska težina 120.714 Da.[7]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MKIATVSVLL | PLALCLIQDA | ASKNEDQEMC | HEFQAFMKNG | KLFCPQDKKF | ||||
| FQSLDGIMFI | NKCATCKMIL | EKEAKSQKRA | RHLARAPKAT | APTELNCDDF | ||||
| KKGERDGDFI | CPDYYEAVCG | TDGKTYDNRC | ALCAENAKTG | SQIGVKSEGE | ||||
| CKSSNPEQDV | CSAFRPFVRD | GRLGCTREND | PVLGPDGKTH | GNKCAMCAEL | ||||
| FLKEAENAKR | EGETRIRRNA | EKDFCKEYEK | QVRNGRLFCT | RESDPVRGPD | ||||
| GRMHGNKCAL | CAEIFKQRFS | EENSKTDQNL | GKAEEKTKVK | REIVKLCSQY | ||||
| QNQAKNGILF | CTRENDPIRG | PDGKMHGNLC | SMCQAYFQAE | NEEKKKAEAR | ||||
| ARNKRESGKA | TSYAELCSEY | RKLVRNGKLA | CTRENDPIQG | PDGKVHGNTC | ||||
| SMCEVFFQAE | EEEKKKKEGK | SRNKRQSKST | ASFEELCSEY | RKSRKNGRLF | ||||
| CTRENDPIQG | PDGKMHGNTC | SMCEAFFQQE | ERARAKAKRE | AAKEICSEFR | ||||
| DQVRNGTLIC | TREHNPVRGP | DGKMHGNKCA | MCASVFKLEE | EEKKNDKEEK | ||||
| GKVEAEKVKR | EAVQELCSEY | RHYVRNGRLP | CTRENDPIEG | LDGKIHGNTC | ||||
| SMCEAFFQQE | AKEKERAEPR | AKVKREAEKE | TCDEFRRLLQ | NGKLFCTREN | ||||
| DPVRGPDGKT | HGNKCAMCKA | VFQKENEERK | RKEEEDQRNA | AGHGSSGGGG | ||||
| GNTQDECAEY | REQMKNGRLS | CTRESDPVRD | ADGKSYNNQC | TMCKAKLERE | ||||
| AERKNEYSRS | RSNGTGSESG | KDTCDEFRSQ | MKNGKLICTR | ESDPVRGPDG | ||||
| KTHGNKCTMC | KEKLEREAAE | KKKKEDEDRS | NTGERSNTGE | RSNDKEDLCR | ||||
| EFRSMQRNGK | LICTRENNPV | RGPYGKMHIN | KCAMCQSIFD | REANERKKKD | ||||
| EEKSSSKPSN | NAKDECSEFR | NYIRNNELIC | PRENDPVHGA | DGKFYTNKCY | ||||
| MCRAVFLTEA | LERAKLQEKP | SHVRASQEED | SPDSFSSLDS | EMCKDYRVLP | ||||
| RIGYLCPKDL | KPVCGDDGQT | YNNPCMLCHE | NLIRQTNTHI | RSTGKCEESS | ||||
| TPGTTAASMP | PSDE |
Struktura i funkcija
urediLEKTI je velika multidomenska serin-proteaza, inhibitor koji je eksprimiran u slojevitom epitelnom tkivu. Sastoji se od 15 domena koji se cijepaju na manje funkcionalne fragmente pomoću proteaze furina. Samo dva od ovih domena (2 i 15) sadrže po šest ravnomjerno raspoređenih cisteina, odgovornih za tri intramolekulske disulfidne veze karakteristične za inhibitore povezane sa tipom Kazal . Preostali domen sadrže po četiri cisteina.<eef name="furio"/> Ove disulfidne veze prisiljavaju molekule na krutu konformaciju koja omogućava proteinu da stupi u interakciju s ciljanom proteazom putem proširenog beta-lista. Svi domeni (osim 1, 2 i 15) sadrže arginin na P1, što ukazuje da su vjerovatne mete proteaze slične tripsinu.[8]
U epidermi, LEKTI je uključen u regulaciju deskvamacija, svojom sposobnošću da selektivno inhibira KLK5, KLK7 i KLK14.[9] Puna dužina recombinantnog LEKTI-ija inhibira egzogene serinske proteaze: tripsin, plazmin, subtilizin A, katepsin G i ljudske neutrofilne elasteze.[10]
LEKTI može imati ulogu u morfogenezi kože i dlaka i antiupalnoj i/ili antimikrobnoj zaštiti epitela sluzokoža.[6]
Gen
urediSPINK5 je član klastera genske porodice koji se nalazi na hromosomu 5, regija q32,[11] koji kodiraju inhibitore serin-proteaza. Ovo uključuje i druge epidermne proteine, SPINK6 i LEKTI-2 (SPINK9). Gen "SPINK5" je dug 61 kb i sadrži 33 egzona.[8] Alternativna prerada SPINK5 rezultira stvaranjem tri različita genska proizvoda, koji su identificirani u diferenciranim keratinocitima.[12]
Klinički značaj
urediMutacije u genu SPINK5 rezultiraju Nethertonovim sindromom, poremećajem koji karakterizira ihtioza i specifična oštećenja imunoskog sistema.[6]
Reference=
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000133710 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055561 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Magert HJ, Standker L, Kreutzmann P, Zucht HD, Reinecke M, Sommerhoff CP, Fritz H, Forssmann WG (Aug 1999). "LEKTI, a novel 15-domain type of human serine proteinase inhibitor". J Biol Chem. 274 (31): 21499–502. doi:10.1074/jbc.274.31.21499. PMID 10419450.
- ^ a b c "Entrez Gene: SPINK5 serine peptidase inhibitor, Kazal type 5".
- ^ "UniProt, Q9NQ38" (jezik: engleski). Pristupljeno 20. 10. 2021.
- ^ a b Furio L, Hovnanian A (novembar 2011). "When Activity Requires Breaking Up: LEKTI Proteolytic Activation Cascade for Specific Proteinase Inhibition". J Invest Dermatol. 131 (11): 2169–73. doi:10.1038/jid.2011.295. PMID 21997416.
- ^ Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, Wagberg F, Brattsand M, Hachem JP, Leonardsson G, Hovnanian A (septembar 2007). "LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction". Mol. Biol. Cell. 18 (9): 3607–19. doi:10.1091/mbc.E07-02-0124. PMC 1951746. PMID 17596512.
- ^ Mitsudo K, Jayakumar A, Henderson Y, Frederick MJ, Kang Y, Wang M, El-Naggar AK, Clayman GL (april 2003). "Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis". Biochemistry. 42 (13): 3874–81. doi:10.1021/bi027029v. PMID 12667078.
- ^ "SPINK5 serine peptidase inhibitor, Kazal type 5 [Homo sapiens (human)] - Gene - NCBI".
- ^ Tartaglia-Polcini A, Bonnart C, Micheloni A, Cianfarani F, Andrè A, Zambruno G, Hovnanian A, D'Alessio M (februar 2006). "SPINK5, the defective gene in netherton syndrome, encodes multiple LEKTI isoforms derived from alternative pre-mRNA processing". J Invest Dermatol. 126 (2): 315–24. doi:10.1038/sj.jid.5700015. PMID 16374478.
Dopunska literatura
uredi- Norgett EE, Kelsell DP (2002). "SPINK5: both rare and common skin disease". Trends in Molecular Medicine. 8 (1): 7. doi:10.1016/S1471-4914(01)02228-6. PMID 11796258.
- Mägert HJ, Kreutzmann P, Ständker L, et al. (2002). "LEKTI: a multidomain serine proteinase inhibitor with pathophysiological relevance". Int. J. Biochem. Cell Biol. 34 (6): 573–6. doi:10.1016/S1357-2725(01)00179-0. PMID 11943586.
- Walden M, Kreutzmann P, Drögemüller K, et al. (2003). "Biochemical features, molecular biology and clinical relevance of the human 15-domain serine proteinase inhibitor LEKTI". Biol. Chem. 383 (7–8): 1139–41. doi:10.1515/BC.2002.124. PMID 12437098. S2CID 26084613.
- Chavanas S, Garner C, Bodemer C, et al. (2000). "Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping". Am. J. Hum. Genet. 66 (3): 914–21. doi:10.1086/302824. PMC 1288172. PMID 10712206.
- Chavanas S, Bodemer C, Rochat A, et al. (2000). "Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome". Nat. Genet. 25 (2): 141–2. doi:10.1038/75977. PMID 10835624. S2CID 40421711.
- Sprecher E, Chavanas S, DiGiovanna JJ, et al. (2001). "The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis". J. Invest. Dermatol. 117 (2): 179–87. doi:10.1046/j.1523-1747.2001.01389.x. PMID 11511292.
- Walley AJ, Chavanas S, Moffatt MF, et al. (2001). "Gene polymorphism in Netherton and common atopic disease". Nat. Genet. 29 (2): 175–8. doi:10.1038/ng728. PMID 11544479. S2CID 20292050.
- Ahmed A, Kandola P, Ziada G, Parenteau N (2002). "Purification and partial amino acid sequence of proteins from human epidermal keratinocyte conditioned medium". J. Protein Chem. 20 (4): 273–8. doi:10.1023/A:1010902815953. PMID 11594460. S2CID 11877191.
- Bitoun E, Chavanas S, Irvine AD, et al. (2002). "Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families". J. Invest. Dermatol. 118 (2): 352–61. doi:10.1046/j.1523-1747.2002.01603.x. PMID 11841556.
- Komatsu N, Takata M, Otsuki N, et al. (2002). "Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides". J. Invest. Dermatol. 118 (3): 436–43. doi:10.1046/j.0022-202x.2001.01663.x. PMID 11874482.
- Bitoun E, Micheloni A, Lamant L, et al. (2004). "LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome". Hum. Mol. Genet. 12 (19): 2417–30. doi:10.1093/hmg/ddg247. PMID 12915442.
- Nishio Y, Noguchi E, Shibasaki M, et al. (2004). "Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese". Genes Immun. 4 (7): 515–7. doi:10.1038/sj.gene.6363889. PMID 14551605.
- Raghunath M, Tontsidou L, Oji V, et al. (2004). "SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases". J. Invest. Dermatol. 123 (3): 474–83. doi:10.1111/j.0022-202X.2004.23220.x. PMID 15304086.
- Tidow H, Lauber T, Vitzithum K, et al. (2004). "The solution structure of a chimeric LEKTI domain reveals a chameleon sequence" (PDF). Biochemistry. 43 (35): 11238–47. doi:10.1021/bi0492399. PMID 15366933. Arhivirano s originala (PDF), 20. 10. 2021. Pristupljeno 20. 10. 2021.
- Yang T, Liang D, Koch PJ, et al. (2004). "Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice". Genes Dev. 18 (19): 2354–8. doi:10.1101/gad.1232104. PMC 522985. PMID 15466487.
- Ishida-Yamamoto A, Deraison C, Bonnart C, et al. (2005). "LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum". J. Invest. Dermatol. 124 (2): 360–6. doi:10.1111/j.0022-202X.2004.23583.x. PMID 15675955.