Disease relevance of Spn1

• These diseases, ranging from thrombosis to dementia, arise from mutations causing a conformational instability of serpin protease inhibitors [1].
• Polymerization of members of the serpin superfamily underlies diseases as diverse as cirrhosis, angioedema, thrombosis and dementia [2].
• Serpin mechanism of hepatitis C virus nonstructural 3 (NS3) protease inhibition: induced fit as a mechanism for narrow specificity [3].
• Our results also reveal a novel cofactor-induced serpin mechanism of enzyme inhibition that could be explored for developing effective and selective inhibitors of other important induced fit viral proteases of the Flaviviridae family such as the West Nile virus NS3 endoprotease [3].

High impact information on Spn1

• The identification of Spn4A, the most potent and effective natural serpin of PCs identified to date, suggests that Spn4A could be a prototype of endogenous serpins involved in the precise regulation of PC-dependent proteolytic cleavage events in the secretory pathway of eukaryotic cells [4].
• Necrotic is a member of the serine protease inhibitor or serpin superfamily [5].
• Inhibitory activity of the Drosophila melanogaster serpin Necrotic is dependent on lysine residues in the D-helix [5].
• We show that altering the SP6 reactive site loop (RSL) resulted in the development of the first effective (K(i) of 34 nm) and selective serpin, SP6(EVC/S), directed at the NS3 protease [3].
• Many serine proteinase inhibitors of the serpin superfamily have evolved in vertebrates and invertebrates to regulate serine proteinase cascades that mediate the host defense responses [6].

Biological context of Spn1

• The Spn4 gene encodes at least two different serpin proteins, generated by alternate splicing of the last coding exon [7].
• The serpin gene Spn4 from Drosophila melanogaster encodes multiple isoforms with alternative reactive site loops (RSL) [8].
• By applying homology-search and text-mining programs we have found that the Drosophila serine protease inhibitor (serpin) gene sp4 harbours four reactive centre-coding exons [9].
• An examination revealed the presence of two serpin genes, each coding for two or three likely alternative reactive centre exon cassettes, respectively, also in the Caenorhabditis elegans genome [9].
• This role is strikingly analogous to the function of the mammalian serpin antithrombin in localizing the blood-clotting cascade, suggesting that serpin inhibition of protease activity may be a general mechanism for achieving spatial control in diverse biological processes [10].

Anatomical context of Spn1

• Identification, characterization, and functional analysis of sp1 transcript variants expressed in germ cells during mouse spermatogenesis [11].
• A Drosophila gene encoding multiple splice variants of Kazal-type serine protease inhibitor-like proteins with potential destinations of mitochondria, cytosol and the secretory pathway [12].
• Molecular phylogeny of the antiangiogenic and neurotrophic serpin, pigment epithelium derived factor in vertebrates [13].

Associations of Spn1 with chemical compounds

• These data demonstrate a critical role for basic residues within the D-helix (and lysine 68 in particular) in the inhibitory mechanism of the serpin Necrotic [5].
• Necrotic carries a polyglutamine extension amino-terminal to the core serpin structure [14].
• They included protein-folding and stress-response proteins, a hormone, a lipase, a serpin, a cysteine-rich protein and two peptidases, a pro-enzyme form of a cathepsin K-like cysteine peptidase and a gamma-glutamyl transpeptidase [15].

Regulatory relationships of Spn1

• Here, we describe how a serpin controls the serine protease cascade, leading to Toll pathway activation [16].

Other interactions of Spn1

• Acp76A is a 388 amino acid pro-protein which contains a signature sequence for the serpin class of protease inhibitors [17].
• Both full-length Necrotic and the core serpin are active inhibitors of a range of serine proteinases: the highest affinity being for cathepsin G and elastases [14].

Analytical, diagnostic and therapeutic context of Spn1

• Here we describe the molecular cloning and functional expression of a novel member of the serpin family, Serine protease inhibitor 4 (Spn4), that we propose is involved in the regulation of peptide maturation in Drosophila [7].

References