Serpins Flex Their Muscle

Serpins compose the largest superfamily of peptidase inhibitors and are well known as regulators of hemostasis and thrombolysis. Studies using model organisms, from plants to vertebrates, now show that serpins and their unique inhibitory mechanism and conformational flexibility are exploited to control proteolysis in molecular pathways associated with cell survival, development, and host defense. In addition, an increasing number of non-inhibitory serpins are emerging as important elements within a diversity of biological systems by serving as chaperones, hormone transporters, or anti-angiogenic factors.

[1]  P. Bird Regulation of pro‐apoptotic leucocyte granule serine proteinases by intracellular serpins , 1999, Immunology and cell biology.

[2]  D. Gubb,et al.  Uptake of the Necrotic Serpin in Drosophila melanogaster via the Lipophorin Receptor-1 , 2009, PLoS genetics.

[3]  J. Whisstock,et al.  The Serpins Are an Expanding Superfamily of Structurally Similar but Functionally Diverse Proteins , 2001, The Journal of Biological Chemistry.

[4]  P. Carmeliet,et al.  Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. , 1993, The Journal of clinical investigation.

[5]  P. Bird,et al.  The Intracellular Granzyme B Inhibitor, Proteinase Inhibitor 9, Is Up-Regulated During Accessory Cell Maturation and Effector Cell Degranulation, and Its Overexpression Enhances CTL Potency1 , 2003, The Journal of Immunology.

[6]  D. Inzé,et al.  Serpin1 of Arabidopsis thaliana is a suicide inhibitor for metacaspase 9. , 2006, Journal of molecular biology.

[7]  B. Lemaître,et al.  A serpin that regulates immune melanization in the respiratory system of Drosophila. , 2008, Developmental cell.

[8]  M. Ashburner,et al.  Constitutive activation of toll-mediated antifungal defense in serpin-deficient Drosophila. , 1999, Science.

[9]  P. Curmi,et al.  Arabidopsis AtSerpin1, Crystal Structure and in Vivo Interaction with Its Target Protease RESPONSIVE TO DESICCATION-21 (RD21)* , 2010, The Journal of Biological Chemistry.

[10]  F. Gao,et al.  Maspin plays an essential role in early embryonic development , 2004, Development.

[11]  J. Whisstock,et al.  SERPINB11 Is a New Noninhibitory Intracellular Serpin , 2007, Journal of Biological Chemistry.

[12]  S. Olson,et al.  Exosite Determinants of Serpin Specificity* , 2009, The Journal of Biological Chemistry.

[13]  G. Mirza,et al.  Comparison of human chromosome 6p25 with mouse chromosome 13 reveals a greatly expanded ov-serpin gene repertoire in the mouse. , 2002, Genomics.

[14]  H. Kwaan,et al.  The Plasminogen Activator System and Cancer , 2007, Pathophysiology of Haemostasis and Thrombosis.

[15]  J. Whisstock,et al.  Molecular gymnastics: serpin structure, folding and misfolding. , 2006, Current opinion in structural biology.

[16]  P. Carmeliet,et al.  Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization. , 1993, The Journal of clinical investigation.

[17]  S. Itohara,et al.  Embryonic Lethality of Molecular Chaperone Hsp47 Knockout Mice Is Associated with Defects in Collagen Biosynthesis , 2000, The Journal of cell biology.

[18]  B. Lemaître,et al.  An immune-responsive Serpin regulates the melanization cascade in Drosophila. , 2002, Developmental cell.

[19]  G. Silverman,et al.  The Caenorhabditis elegans muscle specific serpin, SRP-3, neutralizes chymotrypsin-like serine peptidases. , 2006, Biochemistry.

[20]  P. Bird,et al.  Control of granzymes by serpins , 2010, Cell Death and Differentiation.

[21]  L. Weiss,et al.  Spatial regulation of developmental signaling by a serpin. , 2003, Developmental cell.

[22]  J. Whisstock,et al.  Serpins Flex Their Muscle , 2010, The Journal of Biological Chemistry.

[23]  M. Belvin,et al.  A serpin mutant links Toll activation to melanization in the host defence of Drosophila , 2002, The EMBO journal.

[24]  D. Gubb,et al.  Immune challenge induces N-terminal cleavage of the Drosophila serpin Necrotic. , 2006, Insect biochemistry and molecular biology.

[25]  J. Whisstock,et al.  X‐ray crystal structure of MENT: evidence for functional loop–sheet polymers in chromatin condensation , 2006, The EMBO journal.

[26]  J. Reichhart,et al.  Tip of another iceberg: Drosophila serpins. , 2005, Trends in cell biology.

[27]  W. Pavan,et al.  Acinar Cell Apoptosis in Serpini2-Deficient Mice Models Pancreatic Insufficiency , 2005, PLoS genetics.

[28]  J. Whisstock,et al.  Human clade B serpins (ov-serpins) belong to a cohort of evolutionarily dispersed intracellular proteinase inhibitor clades that protect cells from promiscuous proteolysis , 2004, Cellular and Molecular Life Sciences CMLS.

[29]  I. Kato,et al.  Mutation-, Aging-, and Gene Dosage-dependent Accumulation of Neuroserpin (G392E) in Endoplasmic Reticula and Lysosomes of Neurons in Transgenic Mice* , 2008, Journal of Biological Chemistry.

[30]  Simon C Watkins,et al.  An Intracellular Serpin Regulates Necrosis by Inhibiting the Induction and Sequelae of Lysosomal Injury , 2007, Cell.

[31]  S. Roth,et al.  A Serpin Regulates Dorsal-Ventral Axis Formation in the Drosophila Embryo , 2003, Current Biology.

[32]  C. Sigmund,et al.  Genetic Ablation of Angiotensinogen in the Subfornical Organ of the Brain Prevents the Central Angiotensinergic Pressor Response , 2006, Circulation research.

[33]  S. Grigoryev,et al.  Cathepsin L Stabilizes the Histone Modification Landscape on the Y Chromosome and Pericentromeric Heterochromatin , 2006, Molecular and Cellular Biology.

[34]  B. Lemaître,et al.  Drosophila Serpin-28D regulates hemolymph phenoloxidase activity and adult pigmentation. , 2008, Developmental biology.

[35]  J. Bednar,et al.  MENT, a Heterochromatin Protein That Mediates Higher Order Chromatin Folding, Is a New Serpin Family Member* , 1999, The Journal of Biological Chemistry.

[36]  J. Hoffmann,et al.  Activation of Drosophila Toll During Fungal Infection by a Blood Serine Protease , 2002, Science.

[37]  J. Hoffmann,et al.  Drosophila innate immunity: an evolutionary perspective , 2002, Nature Immunology.

[38]  C. Sorenson,et al.  PEDF-deficient mice exhibit an enhanced rate of retinal vascular expansion and are more sensitive to hyperoxia-mediated vessel obliteration. , 2008, Experimental eye research.

[39]  D. Lomas,et al.  Molecular and Cellular Aspects of the Serpinopathies and Disorders in Serpin Activity , 2007 .

[40]  H. Ragg,et al.  Functional diversification of a protease inhibitor gene in the genus Drosophila and its molecular basis. , 2008, Gene.

[41]  U. Hengst,et al.  Male fertility defects in mice lacking the serine protease inhibitor protease nexin-1 , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[42]  H. Ha,et al.  The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases , 2009, Nature Reviews Nephrology.

[43]  D. Gubb,et al.  Identification and analysis of serpin-family genes by homology and synteny across the 12 sequenced Drosophilid genomes , 2009, BMC Genomics.

[44]  P. Bird,et al.  Targeted Disruption of SPI3/Serpinb6 Does Not Result in Developmental or Growth Defects, Leukocyte Dysfunction, or Susceptibility to Stroke , 2004, Molecular and Cellular Biology.

[45]  J. Trapani,et al.  A New Family of 10 Murine Ovalbumin Serpins Includes Two Homologs of Proteinase Inhibitor 8 and Two Homologs of the Granzyme B Inhibitor (Proteinase Inhibitor 9)* , 1997, The Journal of Biological Chemistry.

[46]  K. Rodenburg,et al.  The Spn4 gene from Drosophila melanogaster is a multipurpose defence tool directed against proteases from three different peptidase families. , 2007, The Biochemical journal.

[47]  B. Lemaître,et al.  A single modular serine protease integrates signals from pattern-recognition receptors upstream of the Drosophila Toll pathway , 2009, Proceedings of the National Academy of Sciences.

[48]  D. Gubb,et al.  Three Pairs of Protease-Serpin Complexes Cooperatively Regulate the Insect Innate Immune Responses* , 2009, The Journal of Biological Chemistry.

[49]  K. Dewar,et al.  Comparative genomic analysis of the clade B serpin cluster at human chromosome 18q21: amplification within the mouse squamous cell carcinoma antigen gene locus. , 2004, Genomics.

[50]  B. Birren,et al.  SERPINB12 Is a Novel Member of the Human ov-serpin Family That Is Widely Expressed and Inhibits Trypsin-like Serine Proteinases* , 2001, The Journal of Biological Chemistry.

[51]  H. Schulz,et al.  Hyporesponsiveness to Glucocorticoids in Mice Genetically Deficient for the Corticosteroid Binding Globulin , 2006, Molecular and Cellular Biology.

[52]  Y. Ashok Drosophila Toll Pathway: The New Model , 2009, Science Signaling.

[53]  M. Noguchi,et al.  Disruption of the Murine α1-Antitrypsin/PI2 Gene , 2004 .

[54]  A M Lesk,et al.  Phylogeny of the serpin superfamily: implications of patterns of amino acid conservation for structure and function. , 2000, Genome research.

[55]  J. Hejgaard,et al.  Serpins in plants and green algae , 2008, Functional & Integrative Genomics.

[56]  R. Zeller,et al.  Protease nexin 1 and its receptor LRP modulate SHH signalling during cerebellar development , 2007, Development.

[57]  J. Meijers,et al.  Absence of mutations in the PCI gene in subfertile men. , 2004, Molecular human reproduction.

[58]  J. Whisstock,et al.  An overview of the serpin superfamily , 2006, Genome Biology.

[59]  K. Suzuki,et al.  The multi‐functional serpin, protein C inhibitor: beyond thrombosis and hemostasis , 2008, Journal of thrombosis and haemostasis : JTH.

[60]  P. Sonderegger,et al.  An Inhibitor of Serine Proteases, Neuroserpin, Acts as a Neuroprotective Agent in a Mouse Model of Neurodegenerative Disease , 2006, Journal of Neuroscience.

[61]  D. R. Mills,et al.  SRP-2 Is a Cross-class Inhibitor That Participates in Postembryonic Development of the Nematode Caenorhabditis elegans , 2004, Journal of Biological Chemistry.

[62]  J. Reichhart,et al.  Sensing of 'danger signals' and pathogen-associated molecular patterns defines binary signaling pathways 'upstream' of Toll , 2008, Nature Immunology.

[63]  S. Sweeney,et al.  Genetic screen identifies serpin5 as a regulator of the toll pathway and CHMP2B toxicity associated with frontotemporal dementia , 2009, Proceedings of the National Academy of Sciences.

[64]  J. Huntington Shape-shifting serpins--advantages of a mobile mechanism. , 2006, Trends in biochemical sciences.