Accelerated Evolution in Inhibitor Domains of Porcine Elafin Family Members

Tamechika, Ichiro; Itakura, Makoto; Saruta, Yoko; Furukawa, Makoto; Kato, Akira; Tachibana, Shinro; Hirose, Shigehisa

doi:10.1074/jbc.271.12.7012

Cited by 42 publications

(41 citation statements)

References 43 publications

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“…1B). This two-exon structure is different from the three-exon structure of the previously determined trappin genes of other animals, in which the third exon codes almost exclusively for the 3Ј-noncoding region (19,20). Because the 3Ј-untranslated region of exon 2 shares significant sequence identity with intron 2 and exon 3 of other trappin genes (for example, GenBank TM accession numbers AB161364 and D13156) (data not shown), the two-exon structure of the guinea pig trappin gene is therefore most likely due to skipping the splice site in the second intron in the guinea pig lineage (Fig.…”

Section: Resultscontrasting

confidence: 57%

“…Pig trappin genes have undergone accelerated evolution (positive Darwin selection) in the protease-binding site. The accelerated evolution of pig trappin genes was caused by mutations (20), but the rapid evolution seen in the guinea pig lineage was due mainly to deletion of the TGS domain or the WAP motif or the rapid elongation of the TGS domain. It is conceivable that the selective force for rapid evolution is sperm competition, sexual selection, and/or sexual conflict (51).…”

Section: Table Imentioning

confidence: 99%

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Identification, Evolution, and Regulation of Expression of Guinea Pig Trappin with an Unusually Long Transglutaminase Substrate Domain

Furutani

Kato

Fibriani

et al. 2005

Journal of Biological Chemistry

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Trappins are found in human, bovine, hippopotamus, and members of the pig family, but not in rat and mouse. To clarify the evolution of the trappin genes and the functional significance of their products, we isolated the trappin gene in guinea pig, a species belonging to a rodent family distinct from rat and mouse. Guinea pig trappin was confirmed to encode the same domain structure as trappin, consisting of a signal sequence, an extra large transglutaminase substrate domain, and a whey acidic protein motif. Northern blot analysis and in situ hybridization histochemistry as well as immunohistochemistry demonstrated that guinea pig trappin is expressed solely in the secretory epithelium of the seminal vesicle and that its expression is androgen-dependent. We confirmed that guinea pig trappin is crosslinked by prostate transglutaminase and that the whey acidic protein motif derived from guinea pig trappin has an inhibitory activity against leukocyte elastase. Genome sequence analysis showed that guinea pig trappin belongs to the family of REST (rapidly evolving seminal vesicle transcribed) genes.Trappins are a family of secreted proteins composed of two domains: a transglutaminase substrate (TGS) 1 domain and a whey acidic protein (WAP) motif (1). The TGS domain serves as an anchoring sequence through which trappins become covalently trapped at the site of action (2, 3). Covalent anchoring is mediated by transglutaminase, a Ca 2ϩ -dependent enzyme that catalyzes cross-linking of proteins between Lys and Gln side chains (4 -6). The WAP motif comprises eight Cys residues that form four disulfide bonds in a conserved arrangement. This four-disulfide core structure was first described in whey acidic protein in mouse milk and thus was named the "WAP motif" (7). Members of the family of WAP motif proteins contain one to three WAP motifs, many of which have proteinase inhibitor activity and/or antibacterial activity (8, 9). Trappins are unique in having TGS domains in their N termini among diverse family members of WAP motif-containing proteins that include toxins, pollen allergens, serine proteinase inhibitors, growth inhibitors, calcium transport inhibitors, and others whose functions have not yet been determined (10 -17).The two-domain structure of trappins suggested that such a combined structure might have evolved by exon shuffling between ancestral genes for a TGS protein and a WAP motif protein. Determination of the structures of trappin genes by us (18 -20) and those of the semenogelin or seminal vesicle clotting protein (SVP) genes (21-23) indeed revealed a significant similarity between the trappin genes and the semenogelin or SVP genes that encode TGSs and are collectively called REST (rapidly evolving seminal vesicle transcribed) genes. Furthermore, phylogenetic analysis of the WAP motif sequences indicated that the WAP signature sequence of trappins is most closely related to the second WAP motif of the secretory leukocyte proteinase inhibitor (SLPI), which has two WAP motifs in tandem (18). These findings ...

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Section: Resultscontrasting

confidence: 57%

Section: Table Imentioning

confidence: 99%

Identification, Evolution, and Regulation of Expression of Guinea Pig Trappin with an Unusually Long Transglutaminase Substrate Domain

Furutani

Kato

Fibriani

et al. 2005

Journal of Biological Chemistry

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“…The hexapeptide repeats in the Trappins are grouped in the second and third blocks of the alignment. As pointed out by Tamechika et al (16), expansion and contraction of the number of hexapeptides in this gene family occur readily, presumably as a result of gene conversions and DNA polymerase slippage. Some sequence similarities suggestive of conversions among the three porcine Trappin genes are underlined.…”

Section: Cross-linking Of the Biotinylated Peptides To Purified Protementioning

confidence: 83%

“…The homology in the putative active site of both simian and bovine SKALP/elafin suggests that these molecules could be elastase inhibitors, although we have no data from functional studies to substantiate this contention. It was, however, shown recently that the porcine SKALP/elafin ortholog is indeed an inhibitor of at least porcine pancreatic elastase (16).…”

Section: Cloning and Sequence Analysis Of Bovine And Simian Skalp/elamentioning

confidence: 96%

“…SKALP/elafin is distinct from SPAI-2 on the basis of its inhibitory activity, the amino acid sequence of the putative active site, and the epithelial expression pattern. The cDNAs and genes for porcine SPAI-2 (2, 3), porcine SKALP/elafin (16), human SKALP/elafin (7,17), and a new porcine family member (16) that is more similar to SPAI-2 than to SKALP/elafin, have been cloned and revealed a high degree of conservation in the gene structure and the intronic sequences but a strong sequence divergence in the second exon.…”

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confidence: 99%

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Identification and Sequence Analysis of Two New Members of the SKALP/elafin and SPAI-2 Gene Family

Zeeuwen¹,

Hendriks²,

Jong³

et al. 1997

Journal of Biological Chemistry

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The human epithelial proteinase inhibitor SKALP/elafin and the porcine sodium-potassium ATPase inhibitor SPAI-2 are two highly homologous proteins that share an NH 2 -terminal transglutaminase substrate domain and a COOH-terminal whey acidic protein (WAP) domain. Here we describe the bovine and simian orthologs of SKALP/elafin as well as two new bovine family members that are designated Trappin-4 and Trappin-5 on the basis of a new nomenclature that we propose (Trappin ‫؍‬ TRansglutaminase substrate and WAP motif-containing ProteIN). Sequence analysis of Trappin-4 and Trappin-5 revealed a domain structure that is very similar to SPAI-2 (Trappin-1) and SKALP/elafin (Trappin-2). The transglutaminase substrate motifs are conserved although the number of repeats varies among species and among family members. The sequence of Trappin-4 and Trappin-5 diverges from Trappin-1 and Trappin-2 at the putative reactive site in the WAP domain. The bovine ortholog of Trappin-2 is expressed in tongue and snout epidermis; Trappin-4 is expressed in trachea, ileum, and tongue; and Trappin-5 is expressed at low levels in trachea, as determined by RNase protection and Northern blot analysis. Based on the analysis of 67 transglutaminase substrate repeats as present in all known Trappin gene family members from four different mammalian species a consensus sequence could be established: GlyGln-Asp-Pro-Val-Lys (GQDPVK). Using biotinylated hexapeptide probes we found that the GQDPVK sequence is a very efficient transglutaminase substrate both for guinea pig liver transglutaminase and for epidermal transglutaminase, and it acts as acyl donor as well as acceptor. We propose that the Trappin protein family forms a new group of enzyme inhibitors with various specificities of the WAP domain, which share transglutaminase substrate motifs that can act as an anchoring sequence. Skin-derived antileukoproteinase (SKALP)1 (1) and sodiumpotassium ATPase inhibitor-2 (SPAI-2) (2) are two molecules that share an NH 2 -terminal domain that functions as a transglutaminase (TGase) substrate, and a COOH-terminal whey acidic protein (WAP) domain that harbors an inhibitory activity toward at least two distinct enzymes. Porcine SPAI-2 was the first of these molecules to be described and is expressed mainly in the intestine (3). Human SKALP, otherwise known as elafin (4), or elastase-specific inhibitor (5), is a potent inhibitor of the leukocytic proteinases elastase and proteinase-3 (6, 7). We found that SKALP/elafin is expressed in several human stratifying squamous epithelia, except for epidermis where it is only expressed in the context of inflammation, such as psoriasis or wound healing (8 -10). We mapped the genomic localization of human SKALP/elafin to chromosome 20q12-13 (11). Interestingly, this region contains various other genes involved in TGase-mediated cross-linking processes such as the tissue TGase gene (12), epidermal TGase (13, 14), and the genes coding for semenogelin I and semenogelin II (15), which are also epithelial TGase substrates. SKAL...

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Anisakis simplex:Mutational Bursts in the Reactive Site Centers of Serine Protease Inhibitors from an Ascarid Nematode

Nguyen

Morris

et al. 1998

Experimental Parasitology

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Accelerated Evolution in Inhibitor Domains of Porcine Elafin Family Members

Cited by 42 publications

References 43 publications

Identification, Evolution, and Regulation of Expression of Guinea Pig Trappin with an Unusually Long Transglutaminase Substrate Domain

Identification, Evolution, and Regulation of Expression of Guinea Pig Trappin with an Unusually Long Transglutaminase Substrate Domain

Identification and Sequence Analysis of Two New Members of the SKALP/elafin and SPAI-2 Gene Family

Anisakis simplex:Mutational Bursts in the Reactive Site Centers of Serine Protease Inhibitors from an Ascarid Nematode

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