Homologous Proteins with Different Folds: The Three-dimensional Structures of Domains 1 and 6 of the Multiple Kazal-type Inhibitor LEKTI

Lauber, Thomas; Schulz, Axel; Schweimer, Kristian; Adermann, Knut; Marx, Ute C.

doi:10.1016/s0022-2836(03)00245-6

Cited by 32 publications

(34 citation statements)

References 56 publications

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“…However, the order and arrangement of elements of secondary structure, as well as the overall tertiary structure of Dom1PI, reveal remarkable differences from the wild-type protein. Dom1PI lacks the short 3 10 -helix present in domain 1 (19), instead displaying a loop conformation in this region. Furthermore, Dom1PI exhibits a second -hairpin structure (Figures 2b and 4a).…”

Section: The Secondary and Tertiary Structure Of Dom1pi Is Different mentioning

confidence: 99%

“…Another reason for the disappearance of the 3 10 -helix might be a loss of stabilization of an intrinsically unstable helix by loss of hydrophobic contacts. The NH 2 -terminal end of the 3 10 -helix in wild-type domain 1 comprises two lysines (19) that amplify the helix dipole, therefore being energetically unfavorable (41). The 3 10 -helix, however, is stabilized by contacts between Phe29 and Ile38 that are part of the long COOH-terminal R-helix in the wild-type protein.…”

Section: The Secondary and Tertiary Structure Of Dom1pi Is Different mentioning

confidence: 99%

“…Another similarity in Dom1PI and LEKTI domain 6 is the existence of an exposed potential canonical loop ( Figures 2a,b and 4b). In domain 6, this region acts as a proteinase binding loop (42), leading to temporary trypsin inhibitory activity that is most likely due to enhanced flexibility (19).…”

Section: The Secondary and Tertiary Structure Of Dom1pi Is Different mentioning

confidence: 99%

“…Trypsin inhibitory activity has also been found for natural domain 5 and recombinant domains 8 and 15 (17). In contrast, no proteinase has been found to be inhibited by domain 1 so far, a fact that can be explained on a structural level (19). Despite their significant sequence homology and conserved disulfide pattern, LEKTI domains 1 and 6 exhibit different folding topologies and domain 1 is lacking the canonical loop structure typical of proteinase inhibitors.…”

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confidence: 99%

“…The three-dimensional structure of domain 6 consists of two helices and a -hairpin structure, closely resembling the classical Kazal-type serine proteinase inhibitor fold, including the inhibitory binding loop. In domain 1, the putative P1′ site is followed by a short 3 10 -helix that bends into a long COOH-terminal R-helix, thus lacking the -hairpin observed in domain 6 (19).…”

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confidence: 99%

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The Solution Structure of a Chimeric LEKTI Domain Reveals a Chameleon Sequence

et al. 2004

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The conversion of an R-helical to a -strand conformation and the presence of chameleon sequences are fascinating from the perspective that such structural features are implicated in the induction of amyloid-related fatal diseases. In this study, we have determined the solution structure of a chimeric domain (Dom1PI) from the multidomain Kazal-type serine proteinase inhibitor LEKTI using multidimensional NMR spectroscopy. This chimeric protein was constructed to investigate the reasons for differences in the folds of the homologous LEKTI domains 1 and 6 [Lauber, T., et al. (2003) J. Mol. Biol. 328, 205-219]. In Dom1PI, two adjacent phenylalanine residues (F28 and F29) of domain 1 were substituted with proline and isoleucine, respectively, as found in the corresponding P4′ and P5′ positions of domain 6. The three-dimensional structure of Dom1PI is significantly different from the structure of domain 1 and closely resembles the structure of domain 6, despite the sequence being identical to that of domain 1 except for the two substituted phenylalanine residues and being only 31% identical to the sequence of domain 6. The mutation converted a short 3 10 -helix into an extended loop conformation and parts of the long COOH-terminal R-helix of domain 1 into a -hairpin structure. The latter conformational change occurs in a sequence stretch distinct from the region containing the substituted residues. Therefore, this switch from an R-helical structure to a -hairpin structure indicates a chameleon sequence of seven residues. We conclude that the secondary structure of Dom1PI is determined not only by the local protein sequence but also by nonlocal interactions.

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Section: The Secondary and Tertiary Structure Of Dom1pi Is Different mentioning

confidence: 99%

Section: The Secondary and Tertiary Structure Of Dom1pi Is Different mentioning

confidence: 99%

Section: The Secondary and Tertiary Structure Of Dom1pi Is Different mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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The Solution Structure of a Chimeric LEKTI Domain Reveals a Chameleon Sequence

et al. 2004

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Synthesis of the proteinase inhibitor LEKTI domain 6 by the fragment condensation method and regioselective disulfide bond formation

et al. 2010

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Proteinase inhibitors are of high pharmaceutical interest and are drug candidates for a variety of indications. Specific kallikrein inhibitors are important for their antitumor activity and their potential application to the treatment of skin diseases. In this study we describe the synthesis of domain 6 of the kallikrein inhibitor Lympho-Epithilial Kazal-Type Inhibitor (LEKTI) by the fragment condensation method and site-directed cystine bridge formation. To obtain the linear LEKTI precursor, the condensation was best performed in solution, coupling the protected fragment 1-22 to 23-68. This method yielded LEKTI domain 6 of high purity and equipotent to the recombinantly produced peptide.

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Inhibitors of kallikrein‐related peptidases: An overview

Masurier

Arama

Amri

et al. 2017

Medicinal Research Reviews

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Kallikrein-related peptidases (KLKs) are a family of 15 secreted serine proteases that are involved in various physiological processes. Their activities are subtly regulated by various endogenous inhibitors, ranging from metallic ions to macromolecular entities such as proteins. Furthermore, dysregulation of KLK activity has been linked to several pathologies, including cancer and skin and inflammatory diseases, explaining the numerous efforts to develop KLK-specific pharmacological inhibitors as potential therapeutic agents. In this review, we focus on the huge repertoire of KLKs inhibitors reported to date with a special emphasis on the diversity of their molecular mechanisms of inhibition.

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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

Cited by 32 publications

References 56 publications

The Solution Structure of a Chimeric LEKTI Domain Reveals a Chameleon Sequence

The Solution Structure of a Chimeric LEKTI Domain Reveals a Chameleon Sequence

Synthesis of the proteinase inhibitor LEKTI domain 6 by the fragment condensation method and regioselective disulfide bond formation

Inhibitors of kallikrein‐related peptidases: An overview

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