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Homologous proteins with different folds: the three-dimensional structures of domains 1 and 6 of the multiple Kazal-type inhibitor LEKTI.

Lauber T, Schulz A, Schweimer K, Adermann K, Marx UC
J Mol Biol 328 205-19 (2003)
Cited: 23 times
EuropePMC logo PMID: 12684009

Abstract

We have determined the solution structures of recombinant domain 1 and native domain 6 of the multi-domain Kazal-type serine proteinase inhibitor LEKTI using multi-dimensional NMR spectroscopy. While two of the 15 potential inhibitory LEKTI domains contain three disulfide bonds typical of Kazal-type inhibitors, the remaining 13 domains have only two of these disulfide bridges. Therefore, they may represent a novel type of serine proteinase inhibitor. The first and the sixth LEKTI domain, which have been isolated from human blood ultrafiltrate, belong to this group. In spite of sharing the same disulfide pattern and a sequence identity of about 35% from the first to the fourth cysteine, the two proteins show different structures in this region. The three-dimensional structure of domain 6 consists of two helices and a beta-hairpin structure, and closely resembles the three-dimensional fold of classical Kazal-type serine proteinase inhibitors including the inhibitory binding loop. Domain 6 has been shown to be an efficient, but non-permanent serine proteinase inhibitor. The backbone geometry of its canonical loop is not as well defined as the remaining structural elements, providing a possible explanation for its non-permanent inhibitory activity. We conclude that domain 6 belongs to a subfamily of classical Kazal-type inhibitors, as the third disulfide bond and a third beta-strand are missing. The three-dimensional structure of domain 1 shows three helices and a beta-hairpin, but the central part of the structure differs remarkably from that of domain 6. The sequence adopting hairpin structure in domain 6 exhibits helical conformation in domain 1, and none of the residues within the putative P3 to P3' stretch features backbone angles that resemble those of the canonical loop of known proteinase inhibitors. No proteinase has been found to be inhibited by domain 1. We conclude that domain 1 adopts a new protein fold and is no canonical serine proteinase inhibitor.

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Reviews citing this publication (5)

  1. Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs). Goettig P, Magdolen V, Brandstetter H. Biochimie 92 1546-1567 (2010)
  2. New insights into the functional mechanisms and clinical applications of the kallikrein-related peptidase family. Emami N, Diamandis EP. Mol Oncol 1 269-287 (2007)
  3. Exploiting natural peptide diversity: novel research tools and drug leads. Adermann K, John H, Ständker L, Forssmann WG. Curr Opin Biotechnol 15 599-606 (2004)
  4. Netherton Syndrome: A Genotype-Phenotype Review. Sarri CA, Roussaki-Schulze A, Vasilopoulos Y, Zafiriou E, Patsatsi A, Stamatis C, Gidarokosta P, Sotiriadis D, Sarafidou T, Mamuris Z. Mol Diagn Ther 21 137-152 (2017)
  5. Inhibitors of kallikrein-related peptidases: An overview. Masurier N, Arama DP, El Amri C, Lisowski V. Med Res Rev 38 655-683 (2018)

Articles citing this publication (17)

  1. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, Wagberg F, Brattsand M, Hachem JP, Leonardsson G, Hovnanian A. Mol Biol Cell 18 3607-3619 (2007)
  2. The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10. Jefferson T, Auf dem Keller U, Bellac C, Metz VV, Broder C, Hedrich J, Ohler A, Maier W, Magdolen V, Sterchi E, Bond JS, Jayakumar A, Traupe H, Chalaris A, Rose-John S, Pietrzik CU, Postina R, Overall CM, Becker-Pauly C. Cell Mol Life Sci 70 309-333 (2013)
  3. Transitive homology-guided structural studies lead to discovery of Cro proteins with 40% sequence identity but different folds. Roessler CG, Hall BM, Anderson WJ, Ingram WM, Roberts SA, Montfort WR, Cordes MH. Proc Natl Acad Sci U S A 105 2343-2348 (2008)
  4. Inhibition of human kallikreins 5 and 7 by the serine protease inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI). Schechter NM, Choi EJ, Wang ZM, Hanakawa Y, Stanley JR, Kang Y, Clayman GL, Jayakumar A. Biol Chem 386 1173-1184 (2005)
  5. Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis. Fortugno P, Bresciani A, Paolini C, Pazzagli C, El Hachem M, D'Alessio M, Zambruno G. J Invest Dermatol 131 2223-2232 (2011)
  6. Domain inhibitory and bacteriostatic activities of the five-domain Kazal-type serine proteinase inhibitor from black tiger shrimp Penaeus monodon. Donpudsa S, Tassanakajon A, Rimphanitchayakit V. Dev Comp Immunol 33 481-488 (2009)
  7. Secondary structure switching in Cro protein evolution. Newlove T, Konieczka JH, Cordes MH. Structure 12 569-581 (2004)
  8. A two disulfide bridge Kazal domain from Phytophthora exhibits stable inhibitory activity against serine proteases of the subtilisin family. Tian M, Kamoun S. BMC Biochem 6 15 (2005)
  9. Expression of LEKTI domains 6-9' in the baculovirus expression system: recombinant LEKTI domains 6-9' inhibit trypsin and subtilisin A. Jayakumar A, Kang Y, Mitsudo K, Henderson Y, Frederick MJ, Wang M, El-Naggar AK, Marx UC, Briggs K, Clayman GL. Protein Expr Purif 35 93-101 (2004)
  10. Characterization, kinetics, and possible function of Kazal-type proteinase inhibitors of Chinese white shrimp, Fenneropenaeus chinensis. Wang ZH, Zhao XF, Wang JX. Fish Shellfish Immunol 26 885-897 (2009)
  11. A novel locust (Schistocerca gregaria) serine protease inhibitor with a high affinity for neutrophil elastase. Brillard-Bourdet M, Hamdaoui A, Hajjar E, Boudier C, Reuter N, Ehret-Sabatier L, Bieth JG, Gauthier F. Biochem J 400 467-476 (2006)
  12. Consequences of C-terminal domains and N-terminal signal peptide deletions on LEKTI secretion, stability, and subcellular distribution. Jayakumar A, Kang Y, Henderson Y, Mitsudo K, Liu X, Briggs K, Wang M, Frederick MJ, El-Naggar AK, Bebök Z, Clayman GL. Arch Biochem Biophys 435 89-102 (2005)
  13. Crystal structure of human epidermal kallikrein 7 (hK7) synthesized directly in its native state in E. coli: insights into the atomic basis of its inhibition by LEKTI domain 6 (LD6). Fernández IS, Ständker L, Mägert HJ, Forssmann WG, Giménez-Gallego G, Romero A. J Mol Biol 377 1488-1497 (2008)
  14. Isolation, cDNA cloning, and structure-based functional characterization of oryctin, a hemolymph protein from the coconut rhinoceros beetle, Oryctes rhinoceros, as a novel serine protease inhibitor. Horita S, Ishibashi J, Nagata K, Miyakawa T, Yamakawa M, Tanokura M. J Biol Chem 285 30150-30158 (2010)
  15. Synthesis of the proteinase inhibitor LEKTI domain 6 by the fragment condensation method and regioselective disulfide bond formation. Vasileiou Z, Barlos KK, Gatos D, Adermann K, Deraison C, Barlos K. Biopolymers 94 339-349 (2010)
  16. Characterization and expression analysis of the Spink5 gene, the mouse ortholog of the defective gene in Netherton syndrome. Galliano MF, Roccasecca RM, Descargues P, Micheloni A, Levy E, Zambruno G, D'Alessio M, Hovnanian A. Genomics 85 483-492 (2005)
  17. LEKTI domain 15 is a functional Kazal-type proteinase inhibitor. Vitzithum K, Lauber T, Kreutzmann P, Schulz A, Sommerhoff CP, Rösch P, Marx UC. Protein Expr Purif 57 45-56 (2008)


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