5yhn

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Solution structure of the LEKTI Domain 4

Structural highlights

5yhn is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR, 20 models
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ISK5_HUMAN Defects in SPINK5 are the cause of Netherton syndrome (NETH) [MIM:256500. NETH is an autosomal recessive congenital ichthyosis associated with hair shaft abnormalities and anomalies of the immune system. Typical features are ichthyosis linearis circumflexa, ichthyosiform erythroderma, trichorrhexis invaginata (bamboo hair), atopic dermatitis, and hayfever. High postnatal mortality is due to failure to thrive, infections and hypernatremic dehydration.[1]

Function

ISK5_HUMAN Serine protease inhibitor, probably important for the anti-inflammatory and/or antimicrobial protection of mucous epithelia. Contribute to the integrity and protective barrier function of the skin by regulating the activity of defense-activating and desquamation-involved proteases. Inhibits KLK5, it's major target, in a pH-dependent manner. Inhibits KLK7, KLK14 CASP14, and trypsin.[2] [3] [4]

Publication Abstract from PubMed

Despite being initially identified in the blood filtrate, LEKTI is a 15-domain Kazal-type inhibitor mostly known in the regulation of skin desquamation. In the current study, screening of serine proteases in blood coagulation cascade showed that LEKTI domain 4 has inhibitory activity toward only FXIa, whereas LEKTI domain 6 inhibits both FXIa and FXaB (bovine FXa). Nuclear magnetic resonance structural and dynamic experiments plus molecular dynamics simulation revealed that LEKTI domain 4 has enhanced backbone flexibility at the reactive-site loop. A model of the LEKTI-protease complex revealed that FXaB has a narrower S4 pocket compared with FXIa and hence prefers only small side-chain residues at the P4 position, such as Ala in LEKTI domain 6. Mutational studies combined with a molecular complex model suggest that both a more flexible reactive-site loop and a bulky residue at the P4 position make LEKTI domain 4 a weaker but highly selective inhibitor of FXIa.

Homologous Lympho-Epithelial Kazal-type Inhibitor Domains Delay Blood Coagulation by Inhibiting Factor X and XI with Differential Specificity.,Ramesh K, Lama D, Tan KW, Nguyen VS, Chew FT, Verma CS, Mok YK Structure. 2018 Jun 13. pii: S0969-2126(18)30205-3. doi:, 10.1016/j.str.2018.05.018. PMID:30017565[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
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SPINK5 is a Prognostic Biomarker Associated With the Progression and Prognosis of Laryngeal Squamous Cell Carcinoma Identified by Weighted Gene Co-Expression Network Analysis.
Liu et al. (2022)
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2 other articles
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References

  1. ↑ Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, Bonafe JL, Wilkinson J, Taieb A, Barrandon Y, Harper JI, de Prost Y, Hovnanian A. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet. 2000 Jun;25(2):141-2. PMID:10835624 doi:10.1038/75977
  2. ↑ Magert HJ, Standker L, Kreutzmann P, Zucht HD, Reinecke M, Sommerhoff CP, Fritz H, Forssmann WG. LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J Biol Chem. 1999 Jul 30;274(31):21499-502. PMID:10419450
  3. ↑ Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, Wagberg F, Brattsand M, Hachem JP, Leonardsson G, Hovnanian A. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell. 2007 Sep;18(9):3607-19. Epub 2007 Jun 27. PMID:17596512 doi:10.1091/mbc.E07-02-0124
  4. ↑ Bennett K, Callard R, Heywood W, Harper J, Jayakumar A, Clayman GL, Di WL, Mills K. New role for LEKTI in skin barrier formation: label-free quantitative proteomic identification of caspase 14 as a novel target for the protease inhibitor LEKTI. J Proteome Res. 2010 Aug 6;9(8):4289-94. doi: 10.1021/pr1003467. PMID:20533828 doi:10.1021/pr1003467
  5. ↑ Ramesh K, Lama D, Tan KW, Nguyen VS, Chew FT, Verma CS, Mok YK. Homologous Lympho-Epithelial Kazal-type Inhibitor Domains Delay Blood Coagulation by Inhibiting Factor X and XI with Differential Specificity. Structure. 2018 Jun 13. pii: S0969-2126(18)30205-3. doi:, 10.1016/j.str.2018.05.018. PMID:30017565 doi:http://dx.doi.org/10.1016/j.str.2018.05.018

Contents


PDB ID 5yhn

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