Update of the human and mouse SERPIN gene superfamily
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GENE FAMILY UPDATE
Open Access
Update of the human and mouse SERPIN gene superfamily Claire Heit1, Brian C Jackson1, Monica McAndrews2, Mathew W Wright3, David C Thompson4, Gary A Silverman5, Daniel W Nebert6* and Vasilis Vasiliou1*
Abstract The serpin family comprises a structurally similar, yet functionally diverse, set of proteins. Named originally for their function as serine proteinase inhibitors, many of its members are not inhibitors but rather chaperones, involved in storage, transport, and other roles. Serpins are found in genomes of all kingdoms, with 36 human protein-coding genes and five pseudogenes. The mouse has 60 Serpin functional genes, many of which are orthologous to human SERPIN genes and some of which have expanded into multiple paralogous genes. Serpins are found in tissues throughout the body; whereas most are extracellular, there is a class of intracellular serpins. Serpins appear to have roles in inflammation, immune function, tumorigenesis, blood clotting, dementia, and cancer metastasis. Further characterization of these proteins will likely reveal potential biomarkers and therapeutic targets for disease. Keywords: Serpins, Serine protease inhibitor, Chaperone, Blood clotting, Thrombolysis, Complement, Cell death, Metastatic cancer
Introduction Serpins represent the largest and most functionally diverse family of protease inhibitors. The name serpin originates from the first described function of this family, viz., serine proteinase inhibitors. In their native state, serpins exist as monomeric proteins. Most serpin family members inhibit serine proteinases of the chymotrypsin family [1], thereby inhibiting proteolytic cascades. However, some serpins exhibit functions unrelated to inhibition of catalytic activity, such as hormone transport and other mechanisms. Approximately 1,500 serpin sequences have been identified; they are found in the genomes of all five kingdoms [2]. There are 36 identified human putatively functional proteincoding genes [3]. The serpin superfamily is divided into groups called clades according to their sequence similarity. Clades are classified as A–P, with clades A–I representing human serpins [4].
* Correspondence: [email protected]; [email protected] 6 Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267-0056, USA 1 Department of Pharmaceutical Sciences, Molecular Toxicology and Environmental Health Sciences Program, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA Full list of author information is available at the end of the article
Serpins have well-conserved secondary structures with an exposed reactive center loop (RCL) (Figure 1), which interacts with the protease active site to inhibit protease activity [5]. The ability for serpins to undergo conformational change is crucial for their function, in which serpins act via a suicide substrate inhibitory mechanism [2,4]. Although most serpins selectively inhibit serine proteases, some inhib
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