{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox_gene}} '''Lympho-epithelial Kazal-type-related inhibitor''' (LEKTI) also known as '''serine protease inhibitor Kazal-type 5''' (SPINK5) is a protein that in humans is encoded by the ''SPINK5'' gene.<ref name="pmid10419450">{{cite journal |vauthors=Magert HJ, Standker L, Kreutzmann P, Zucht HD, Reinecke M, Sommerhoff CP, Fritz H, Forssmann WG | title = LEKTI, a novel 15-domain type of human serine proteinase inhibitor | journal = J Biol Chem | volume = 274 | issue = 31 | pages = 21499–502 |date=Aug 1999 | pmid = 10419450 | doi =10.1074/jbc.274.31.21499 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SPINK5 serine peptidase inhibitor, Kazal type 5| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=11005}}</ref>
== Structure and function ==
LEKTI is a large multidomain serine protease inhibitor expressed in stratified epithelial tissue. It consists of 15 domains that are cleaved into smaller, functional fragments by the protease furin. Only two of these domains (2 and 15) contain the 6 evenly spaced cysteines responsible for the 3 intramolecular disulfide bonds that are characteristic of Kazal-type related inhibitors. The remaining domains contain 4 cysteines.<ref name="furio" /> These disulfide bonds force the molecule into a rigid conformation that enables the protein to interact with a target protease via an extended beta-sheet. All domains (excepting 1, 2 and 15) contain an arginine at P1, indicating trypsin-like proteases are the likely targets.<ref name="furio" />
In the epidermis, LEKTI is implicated in the regulation of desquamation via its ability to selectively inhibit KLK5, KLK7 and KLK14.<ref name="pmid17596512">{{cite journal |vauthors=Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, Wagberg F, Brattsand M, Hachem JP, Leonardsson G, Hovnanian A | title = LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction | journal = Mol. Biol. Cell | volume = 18 | issue = 9 | pages = 3607–19 |date=September 2007 | pmid = 17596512 | pmc = 1951746 | doi = 10.1091/mbc.E07-02-0124 }}</ref> Recombinant full length LEKTI inhibits the exogenous serine proteases trypsin, plasmin, subtilisin A, cathepsin G and human neutrophil elastase.<ref name="pmid12667078">{{cite journal |vauthors=Mitsudo K, Jayakumar A, Henderson Y, Frederick MJ, Kang Y, Wang M, El-Naggar AK, Clayman GL | title = Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis. | journal = Biochemistry | volume = 42 | issue = 13 | pages = 3874–81 |date=April 2003 | pmid = 12667078 | doi = 10.1021/bi027029v}}</ref>
LEKTI may play a role in skin and hair morphogenesis and anti-inflammatory and/or antimicrobial protection of mucous epithelia.<ref name="entrez"/>
== Gene ==
''SPINK5'' is a member of a gene family cluster located on chromosome 5q32,<ref>{{Cite web | url=https://www.ncbi.nlm.nih.gov/gene/11005 | title=SPINK5 serine peptidase inhibitor, Kazal type 5 [Homo sapiens (human)] - Gene - NCBI}}</ref> which encode inhibitors of serine proteases. This includes other epidermal proteins SPINK6 and LEKTI-2 (''SPINK9''). The ''SPINK5'' gene is 61 kb in length and contains 33 exons.<ref name="furio"> {{cite journal |vauthors=Furio L, Hovnanian A | title = When Activity Requires Breaking Up: LEKTI Proteolytic Activation Cascade for Specific Proteinase Inhibition. | journal = J Invest Dermatol | volume = 131 | issue = 11 | pages = 2169–73 |date=November 2011 | pmid = 21997416 | doi = 10.1038/jid.2011.295 | doi-access = free }} </ref> Alternative processing of ''SPINK5'' results in the formation of three different gene products, which have been identified in differentiated keratinocytes.<ref name="tartaglia"> {{cite journal |vauthors=Tartaglia-Polcini A, Bonnart C, Micheloni A, Cianfarani F, Andrè A, Zambruno G, Hovnanian A, D'Alessio M | title = SPINK5, the defective gene in netherton syndrome, encodes multiple LEKTI isoforms derived from alternative pre-mRNA processing. | journal = J Invest Dermatol | volume = 126 | issue = 2 | pages = 315–24 |date=February 2006 | pmid = 16374478 | doi = 10.1038/sj.jid.5700015| doi-access = free }} </ref>
== Clinical significance ==
Mutations in the SPINK5 gene result in Netherton syndrome, a disorder characterized by ichthyosis and specific immune system defects.<ref name="entrez"/>
==See also== *Kazal-type serine protease inhibitor domain
==References== {{reflist}}
==Further reading== {{refbegin | 2}} *{{cite journal |vauthors=Norgett EE, Kelsell DP |title=SPINK5: both rare and common skin disease. |journal=Trends in Molecular Medicine |volume=8 |issue= 1 |pages= 7 |year= 2002 |pmid= 11796258 |doi=10.1016/S1471-4914(01)02228-6 }} *{{cite journal |vauthors=Mägert HJ, Kreutzmann P, Ständker L, etal |title=LEKTI: a multidomain serine proteinase inhibitor with pathophysiological relevance. |journal=Int. J. Biochem. Cell Biol. |volume=34 |issue= 6 |pages= 573–6 |year= 2002 |pmid= 11943586 |doi=10.1016/S1357-2725(01)00179-0 }} *{{cite journal |vauthors=Walden M, Kreutzmann P, Drögemüller K, etal |title=Biochemical features, molecular biology and clinical relevance of the human 15-domain serine proteinase inhibitor LEKTI. |journal=Biol. Chem. |volume=383 |issue= 7–8 |pages= 1139–41 |year= 2003 |pmid= 12437098 |doi=10.1515/BC.2002.124 |s2cid=26084613 }} *{{cite journal |vauthors=Chavanas S, Garner C, Bodemer C, etal |title=Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping. |journal=Am. J. Hum. Genet. |volume=66 |issue= 3 |pages= 914–21 |year= 2000 |pmid= 10712206 |doi=10.1086/302824 | pmc=1288172 }} *{{cite journal |vauthors=Chavanas S, Bodemer C, Rochat A, etal |title=Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. |journal=Nat. Genet. |volume=25 |issue= 2 |pages= 141–2 |year= 2000 |pmid= 10835624 |doi= 10.1038/75977 |s2cid=40421711 }} *{{cite journal |vauthors=Sprecher E, Chavanas S, DiGiovanna JJ, etal |title=The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis. |journal=J. Invest. Dermatol. |volume=117 |issue= 2 |pages= 179–87 |year= 2001 |pmid= 11511292 |doi= 10.1046/j.1523-1747.2001.01389.x |doi-access= free }} *{{cite journal |vauthors=Walley AJ, Chavanas S, Moffatt MF, etal |title=Gene polymorphism in Netherton and common atopic disease. |journal=Nat. Genet. |volume=29 |issue= 2 |pages= 175–8 |year= 2001 |pmid= 11544479 |doi= 10.1038/ng728 |s2cid=20292050 }} *{{cite journal |vauthors=Ahmed A, Kandola P, Ziada G, Parenteau N |title=Purification and partial amino acid sequence of proteins from human epidermal keratinocyte conditioned medium. |journal=J. Protein Chem. |volume=20 |issue= 4 |pages= 273–8 |year= 2002 |pmid= 11594460 |doi=10.1023/A:1010902815953 |s2cid=11877191 }} *{{cite journal |vauthors=Bitoun E, Chavanas S, Irvine AD, etal |title=Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. |journal=J. Invest. Dermatol. |volume=118 |issue= 2 |pages= 352–61 |year= 2002 |pmid= 11841556 |doi= 10.1046/j.1523-1747.2002.01603.x |doi-access= free }} *{{cite journal |vauthors=Komatsu N, Takata M, Otsuki N, etal |title=Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides. |journal=J. Invest. Dermatol. |volume=118 |issue= 3 |pages= 436–43 |year= 2002 |pmid= 11874482 |doi= 10.1046/j.0022-202x.2001.01663.x |doi-access= free |hdl= 2297/15796 |hdl-access= free }} *{{cite journal |vauthors=Bitoun E, Micheloni A, Lamant L, etal |title=LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. |journal=Hum. Mol. Genet. |volume=12 |issue= 19 |pages= 2417–30 |year= 2004 |pmid= 12915442 |doi= 10.1093/hmg/ddg247 |doi-access= free }} *{{cite journal |vauthors=Nishio Y, Noguchi E, Shibasaki M, etal |title=Association between polymorphisms in the SPINK5 gene and atopic dermatitis in the Japanese. |journal=Genes Immun. |volume=4 |issue= 7 |pages= 515–7 |year= 2004 |pmid= 14551605 |doi= 10.1038/sj.gene.6363889 |doi-access= free }} *{{cite journal |vauthors=Raghunath M, Tontsidou L, Oji V, etal |title=SPINK5 and Netherton syndrome: novel mutations, demonstration of missing LEKTI, and differential expression of transglutaminases. |journal=J. Invest. Dermatol. |volume=123 |issue= 3 |pages= 474–83 |year= 2004 |pmid= 15304086 |doi= 10.1111/j.0022-202X.2004.23220.x |doi-access= free }} *{{cite journal |vauthors=Tidow H, Lauber T, Vitzithum K, etal |title=The solution structure of a chimeric LEKTI domain reveals a chameleon sequence. |journal=Biochemistry |volume=43 |issue= 35 |pages= 11238–47 |year= 2004 |pmid= 15366933 |doi= 10.1021/bi0492399 |url= http://www.bp.uni-bayreuth.de/Publications/Papers/2004/2004_1.pdf }} *{{cite journal |vauthors=Yang T, Liang D, Koch PJ, etal |title=Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice. |journal=Genes Dev. |volume=18 |issue= 19 |pages= 2354–8 |year= 2004 |pmid= 15466487 |doi= 10.1101/gad.1232104 | pmc=522985 }} *{{cite journal |vauthors=Ishida-Yamamoto A, Deraison C, Bonnart C, etal |title=LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum. |journal=J. Invest. Dermatol. |volume=124 |issue= 2 |pages= 360–6 |year= 2005 |pmid= 15675955 |doi= 10.1111/j.0022-202X.2004.23583.x |doi-access= free }} {{refend}}
== External links == * {{PDBe-KB2|Q9NQ38|Serine protease inhibitor Kazal-type 5}}
{{PDB Gallery|geneid=11005}}
{{gene-5-stub}}