Taxonomic distribution of proteins containing SERPIN domains

The tree below includes only several representative species and genera. The complete taxonomic breakdown of all proteins containing SERPIN domains can be accessed here. Click the counts or percentage values to display the corresponding proteins.

Neuroserpin, an axonally secreted serine protease inhibitor.

Osterwalder T, Contartese J, Stoeckli ET, Kuhn TB, Sonderegger P
EMBO J. 1996; 15: 2944-53

We have identified and chromatographically purified an axonally secreted glycoprotein of CNS and PNS neurons. Several peptides derived from it were microsequenced. Based on these sequences, a fragment of the corresponding cDNA was amplified and used as a probe to isolate a full length cDNA from a chicken brain cDNA library. Because the deduced amino acid sequence qualified the protein as a novel member of the serpin family of serine protease inhibitors, we called it neuroserpin. Analysis of the primary structural features further characterized neuroserpin as a heparin-independent, functional inhibitor of a trypsin-like serine protease. In situ hybridization revealed a predominantly neuronal expression during the late stages of neurogenesis and in the adult brain in regions which exhibit synaptic plasticity. Thus, neuroserpin might function as an axonally secreted regulator of the local extracellular proteolysis involved in the reorganization of the synaptic connectivity during development and synapse plasticity in the adult.

Inhibition of interleukin-1 beta converting enzyme by the cowpox virus serpin CrmA. An example of cross-class inhibition.

Komiyama T, Ray CA, Pickup DJ, Howard AD, Thornberry NA, Peterson EP, Salvesen G
J Biol Chem. 1994; 269: 19331-7

We reported previously that human interleukin-1 beta converting enzyme (ICE) is regulated by the CrmA serpin encoded by cowpox virus. We now report the mechanism and kinetics of this unusual inhibition of a cysteine proteinase by a member of the serpin superfamily previously thought to inhibit serine proteinase only. CrmA possesses several characteristics typical of a number of inhibitory serpins. It is conformationally unstable, unfolding around 3 M urea, and stable to denaturation in 8 M urea upon complex formation with ICE. CrmA rapidly inhibits ICE with an association rate constant (kon) of 1.7 x 10(7) M-1 s-1, forming a tight complex with an equilibrium constant for inhibition (Ki) of less than 4 x 10(-12) M. These data indicate that CrmA is a potent inhibitor of ICE, consistent with the dramatic effects of CrmA on modifying host responses to virus infection. The inhibition of ICE by CrmA is an example of a "cross-class" interaction, in which a serpin inhibits a non-serine proteinase. Since CrmA possesses characteristics shared by inhibitors of serine proteinases, we presume that ICE, though it is a cysteine proteinase, has a substrate binding geometry strikingly close to that of serine proteinases. We reason that it is the substrate binding geometry, not the catalytic mechanism of a proteinase, that dictates its reactivity with protein inhibitors.

Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells.

Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E, Sager R
Science. 1994; 263: 526-9

A gene encoding a protein related to the serpin family of protease inhibitors was identified as a candidate tumor suppressor gene that may play a role in human breast cancer. The gene product, called maspin, is expressed in normal mammary epithelial cells but not in most mammary carcinoma cell lines. Transfection of MDA-MB-435 mammary carcinoma cells with the maspin gene did not alter the cells' growth properties in vitro, but reduced the cells' ability to induce tumors and metastasize in nude mice and to invade through a basement membrane matrix in vitro. Analysis of human breast cancer specimens revealed that loss of maspin expression occurred most frequently in advanced cancers. These results support the hypothesis that maspin functions as a tumor suppressor.

Pigment epithelium-derived factor: neurotrophic activity and identification as a member of the serine protease inhibitor gene family.

Steele FR, Chader GJ, Johnson LV, Tombran-Tink J
Proc Natl Acad Sci U S A. 1993; 90: 1526-30

Cultured pigment epithelial cells of the fetal human retina secrete a protein, pigment epithelium-derived factor (PEDF), that induces a neuronal phenotype in cultured human retinoblastoma cells. Morphological changes include the induction of an extensive neurite meshwork and the establishment of corona-like cellular aggregates surrounding a central lumen. The differentiated cells also show increases in the expression of neuron-specific enolase and the 200-kDa neurofilament subunit. Amino acid and DNA sequence data demonstrate that PEDF belongs to the serine protease inhibitor (serpin) family. The PEDF gene contains a typical signal-peptide sequence, initiator methionine codon, and polyadenylylation signal and matches the size of other members of the serpin superfamily (e.g., alpha 1-antitrypsin). It lacks homology, however, at the putative serpin reactive center. Thus, PEDF could exert a paracrine effect in the embryonic retina, influencing neuronal differentiation by a mechanism that does not involve classic inhibition of serine protease activity.

Cloning of a human collagen-binding protein, and its homology with rat gp46, chick hsp47 and mouse J6 proteins.

Clarke EP, Sanwal BD
Biochim Biophys Acta. 1992; 1129: 246-8

Several cDNA clones encoding a collagen-binding protein were isolated from human fibroblasts. The cDNA encoded a 417 amino acid protein, containing two potential N-linked oligosaccharide binding sites and a C-terminal RDEL sequence, which has been shown to act as an endoplasmic retention signal in other systems. The derived amino acid sequence of the protein shows close homology with gp46 from rat skeletal myoblasts, J6 protein from mouse F9 embryonal carcinoma cells and hsp47 from chick embryo fibroblasts. It also shows sequence similarity with members of the serpin family.

A major estrogen-regulated protein secreted from the liver of Xenopus laevis is a member of the serpin superfamily. Nucleotide sequence of cDNA and hormonal induction of mRNA.

Holland LJ, Suksang C, Wall AA, Roberts LR, Moser DR, Bhattacharya A
J Biol Chem. 1992; 267: 7053-9

Estrogen treatment of Xenopus frogs causes four mRNAs to become highly abundant in the liver. Three of these mRNAs have been previously identified as coding for vitellogenin, ferritin, and serum retinol binding protein. We show here that the fourth abundant liver messenger RNA comprises about 1500 nucleotides and codes for a 45-kDa secreted protein, designated Ep45. A clone complementary to Ep45 mRNA was isolated, and its identity was confirmed by hybridization selection of mRNA that translated in vitro into the Ep45 precursor. Nucleotide sequence analysis of the nearly full length cDNA revealed a total length of 1454 base pairs consisting of: 36 nucleotides of the 5' noncoding region, 1308 base pairs encoding an open reading frame of 436 amino acids, and 110 nucleotides of the 3' untranslated region. Ep45 mRNA may originate from as many as four closely spaced transcription start sites, which are 15 to 21 bases upstream of the first nucleotide of the cDNA clone. The Xenopus laevis genome appears to contain a single Ep45 gene. The deduced amino acid sequence indicates that Ep45 has features typical of a secreted protein, including a signal peptide of 16 amino acids and three potential sites for N-linked glycosylation, and is related to the serine protease inhibitors, a large family of proteins with very diverse physiological functions. Ep45 mRNA was absent in the liver of normal male frogs and increased at least 100-fold in response to estradiol-17 beta. Thus, both Ep45 and vitellogenin mRNAs are switched from undetectable to very high levels, a pattern of expression not found for any other mRNAs in Xenopus liver.

A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors.

Kirchhoff C, Habben I, Ivell R, Krull N
Biol Reprod. 1991; 45: 350-7

The amino acid sequence of a major human epididymis-specific protein was deduced from the nucleotide sequence of its cloned cDNA. The encoded product showed characteristics of a secretory protein, with a signal peptide followed by a small (approximately 10-kDa), acidic (pI 4.3), and cysteine-rich polypeptide. The positions of half-cysteines suggested that it was a two-domain member of the family of 'four-disulfide core' proteins to which a number of proteinase inhibitors belong. Southern blot analyses of human genomic DNA showed that the transcripts originated from a single copy gene. Northern blot and in situ transcript hybridization specifically localized the HE4 (human epididymis gene product) mRNA to the epithelial cells of the epididymal duct, predominantly within the distal sections. A possible function in sperm maturation as indicated by amino acid similarities to extracellular proteinase inhibitors of genital tract mucous secretions is discussed in the context of its tissue-specific transcription.

Implications of the three-dimensional structure of alpha 1-antitrypsin for structure and function of serpins.

Huber R, Carrell RW
Biochemistry. 1989; 28: 8951-66

The serpins: evolution and adaptation in a family of protease inhibitors.

Carrell RW, Pemberton PA, Boswell DR
Cold Spring Harb Symp Quant Biol. 1987; 52: 527-35