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Law, Ruby H. P.; Zhang, Qingwei; McGowan, Sheena; Buckle, Ashley M.; Silverman, Gary A.; Wong, Wilson; Rosado, Carlos J.; Langendorf, Christopher G.; Pike, Robert N.; Bird, Phillip I.; Whisstock, James C.

doi:10.1186/gb-2006-7-5-216

Cited by 598 publications

(326 citation statements)

References 99 publications

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“…The acronym "SERPIN" was originally coined because many serpins inhibit serine proteases (SERine Protease INhibitors). Over 3000 serpins have now been identified; these include 36 human proteins, as well as molecules in plants, fungi, bacteria, archaea and certain viruses [8]. Serpins are thus the largest and most diverse family of protease inhibitors.…”

Section: The Serpin Superfamilymentioning

confidence: 99%

New Caspases’ inhibitors belonging to the serpin superfamily: A novel key control point of apoptosis in mammalian tissues

Gagaoua¹,

Boudida²,

Becila³

et al. 2012

ABB

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The present report overviews a new family of bovine serpins able to inhibit pseudo-irreversibly initiator and effector caspases, a group of cysteine proteases in charge of cell dismantling during apoptosis, a finely regulated cell death process. The 8 members identified at the gene level showed a high homology with human SERPINA3 and were therefore designed bovSERPINA3-1 to A3-8. At least six of them are able to inhibit caspases. Two of them (bovSERPINA3-1 and A3-3) have been purified from bovine muscle and extensively investigated during these last years. After a general presentation of the serpin superfamily, the kinetic aspects of their interaction with human caspases 3 and 8 were studied and findings obtained suggest that caspases could be their target enzymes in living cells. In muscle and primary myoblast in culture, they showed an intracellular localization and because of their high level in blood, they can be exported. Two biological functions (potential regulator of apoptosis and expression during myoblast differentiation) were investigated and it was concluded that they are very likely an efficient regulator of apoptosis, a proposal supported by their high expression in proliferating myoblast (cell survival is essential during this differentiation phase) but not in myotubes.

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Section: The Serpin Superfamilymentioning

confidence: 99%

New Caspases’ inhibitors belonging to the serpin superfamily: A novel key control point of apoptosis in mammalian tissues

Gagaoua¹,

Boudida²,

Becila³

et al. 2012

ABB

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“…The serpin (an acronym for serine protease inhibitor) superfamily constitutes the largest class of protease inhibitors, with more than 1500 members identified to date (Law et al, 2006). They typically consist of a single large domain (of about 350-400 residues in length) with a highly conserved fold.…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional structure of a schistosome serpin revealing an unusual configuration of the helical subdomain

Granzin¹,

Huang²,

Topbaş³

et al. 2012

Acta Crystallogr D Biol Crystallogr

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Parasitic organisms are constantly challenged by the defence mechanisms of their respective hosts, which often depend on serine protease activities. Consequently, protease inhibitors such as those belonging to the serpin superfamily have emerged as protective elements that support the survival of the parasites. This report describes the crystal structure of ShSPI, a serpin from the trematode Schistosoma haematobium. The protein is exposed on the surface of invading cercaria as well as of adult worms, suggesting its involvement in the parasite–host interaction. While generally conforming to the well established serpin fold, the structure reveals several distinctive features, mostly concerning the helical subdomain of the protein. It is proposed that these peculiarities are related to the unique biological properties of a small serpin subfamily which is conserved among pathogenic schistosomes.

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“…The close structural relationship between CBG and AAT defines it as a clade A serine proteinase inhibitor (serpin) family member (5). Many of these serpin A family members, including CBG, are encoded by genes in the human 14q21.1 chromosome cluster and are thought to have arisen by gene duplication to produce serpins with similar properties and physiological functions (6).…”

mentioning

confidence: 99%

Residues in the Human Corticosteroid-binding Globulin Reactive Center Loop That Influence Steroid Binding before and after Elastase Cleavage

Lin

Underhill

Gardill

et al. 2009

Journal of Biological Chemistry

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Corticosteroid-binding globulin (CBG) is a non-inhibitory serine proteinase inhibitor (serpin) that transports cortisol and progesterone in blood. Crystal structures of rat CBG and a thrombin-cleaved human CBG:anti-trypsin (Pittsburgh) chimera show how structural transitions after proteolytic cleavage of the CBG reactive center loop (RCL) could disrupt steroid binding. This ligand release mechanism is assumed to involve insertion of the cleaved RCL into the ␤-sheet A of the serpin structure. We have, therefore, examined how amino acid substitutions in the human CBG RCL influence steroid binding before and after its cleavage by neutrophil elastase. Elastase-cleaved wild-type CBG or variants with substitutions at P15 and/or P16 (E334G/G335N or E334A) lost steroid binding completely, whereas deletion of Glu-334 resulted in no loss of steroid binding after RCL cleavage, presumably because this prevents its insertion into ␤-sheet A. Similarly, the steroid binding properties of CBG variants with substitutions at P15 (G335P), P14 (V336R), or P12 (T338P) in the RCL hinge were largely unaffected after elastase cleavage, most likely because the re-orientation and/or insertion of the cleaved RCL was blocked. Substitutions at P10 (G340P, G340S) or P8 (T342P, T342N) resulted in a partial loss of steroid binding after proteolysis which we attribute to incomplete insertion of the cleaved RCL. Remarkably, several substitutions (E334A, V336R, G340S, and T342P) increased the steroid binding affinities of human CBG even before elastase cleavage, consistent with the concept that CBG normally toggles between a high affinity ligand binding state where the RCL is fully exposed and a lower affinity state in which the RCL is partly inserted into ␤-sheet A. Corticosteroid-binding globulin (CBG)2 is the major carrier protein for natural glucocorticoids (cortisol and corticosterone) and progesterone in blood (1), and it regulates the bioavailability of steroids that control numerous physiological processes including reproduction, inflammation, stress responses, and tissue development (2). Because CBG binds up to 90% of the glucocorticoids in blood plasma, it serves as a reservoir of anti-inflammatory steroids that can be released at their sites of action (3). The latter concept was proposed when it was discovered that human CBG exhibits remarkable sequence identity with the archetypal serine proteinase inhibitor, ␣1-anti-trypsin (AAT), and was based on the realization that CBG might also be a target of specific classes of proteinases (4).The close structural relationship between CBG and AAT defines it as a clade A serine proteinase inhibitor (serpin) family member (5). Many of these serpin A family members, including CBG, are encoded by genes in the human 14q21.1 chromosome cluster and are thought to have arisen by gene duplication to produce serpins with similar properties and physiological functions (6). Unlike most clade A serpins, CBG is not known to act as a proteinase inhibitor but appears to be a suicide substrate of specific protei...

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Untitled

Cited by 598 publications

References 99 publications

New Caspases’ inhibitors belonging to the serpin superfamily: A novel key control point of apoptosis in mammalian tissues

New Caspases’ inhibitors belonging to the serpin superfamily: A novel key control point of apoptosis in mammalian tissues

Three-dimensional structure of a schistosome serpin revealing an unusual configuration of the helical subdomain

Residues in the Human Corticosteroid-binding Globulin Reactive Center Loop That Influence Steroid Binding before and after Elastase Cleavage

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