Serpine

Serpins inhibit serine proteinases with a spring-loaded safety catch mechanism... 

Serpins form very tight complexes with their corresponding serine pro-teinases, thereby inhibiting the latter. A flexible loop region of the serpin binds to the active site of the proteinases. Upon release of the serpin from the complex its polypeptide chain is cleaved by the proteinase in the middle of this loop region and the molecule is subsequently degraded. In addition to the active and cleaved states of the serpins there is also a latent state with an intact polypeptide chain that is functionally inactive and does not bind to the proteinase. 

The setpin fold comprises a compact body of three antiparallel p sheets, A, B and C, which ate partly coveted by a helices (Figure 6.22). In the structure of the uncleaved form of ovalbumin, which can be regarded as the canonical structure of the serpins, sheet A has five strands. The flexible loop starts at the end of strand number 5 of p sheet A (plS in Figure 6.22), then... 

Figure 6,22 Schematic diagram of the structure of ovalbumin which illustrates the serpin fold. The structure is built up of a compact body of three antiparallel p sheets,...

A, B, and C, surrounded by a helices. The polypeptide chain is colored in sections from the N-terminus to facilitate following the chain tracing in the order green, blue, yellow, red and pink. The red region corresponds to the active site loop in the serpins which in ovalbumin is protruding like a handle out of the main body of the structure. (Adapted from R.W. Carrell et al.. Structure 2 257-270, 1994.)... 

Figure 6.23 Schematic diagram illustrating the active site loop regions (red) in three forms of the serpins. (a) In the active form the loop protrudes from the main part of the molecuie poised to interact with the active site of a serine proteinase. The first few residues of the ioop form a short p strand inserted between ps and pis of sheet A. (h) As a result of inhibiting proteases, the serpin molecules are cleaved at the tip of the active site ioop region, in the cleaved form the N-terminal part of the loop inserts itself between p strands 5 and 15 and forms a long p strand (red) in the middie of the p sheet, (c) In the most stable form, the latent form, which is inactive, the N-terminai part of the ioop forms an inserted p strand as in the cleaved form and the remaining residues form a ioop at the other end of the p sheet. (Adapted from R.W. Carreii et ai., Structure 2 257-270, 1994.)...

In viw PAI and antithrombin are stabilized in their active forms by binding to vitronectin and heparin, respectively. These two serpins seem to have evolved what Max Perutz has called "a spring-loaded safety catch" mechanism that makes them revert to their latent, stable, inactive form unless the catch is kept in a loaded position by another molecule. Only when the safety catch is in the loaded position is the flexible loop of these serpins exposed and ready for action otherwise it snaps back and is buried inside the protein. This remarkable biological control mechanism is achieved by the flexibility that is inherent in protein structures. 

Goldsmith, E.J, Mottonen, J. Serpins the uncut version. Structure 2 241-244, 1994. 

Carrell, R.W., Evans, D.F., Stein, RE. Mobile reactive centre of serpins and the control of thrombosis. Nature 353 576-578, 1991. 

Schreuder, H.A., et al. The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions. Nature (Struct. Biol.)... 

Stein, P.E., et al. Crystal stmcture of ovalbumin as a model for the reactive centre of serpins. Nature 347 99-102, 1990. 

Schulze, A. J., Huber, R., Bode, W., and Engh, R. A., 1994. Structural aspects of serpin inhibition. FEES Letters 344 117-124. 

Stein, P. E., and Carrell, R. W., 1995. What do dysfnncUonal serpins tell ns about molecular mobility and disease Nature Structural Biology 2 96-113. 

Plotnick, M. L, Mayne, L., Schechter, N. M., and Rnbiii, H., 1996. Distortion of the active site of chymotrypsin complexed widi a serpin. Biochemistry 35 7586-7590. 

Hydropres-50—hydrochlorothiazide, reserpine Hydro-Seqi—hydrochlorothiazide, reserpine Hydro serpine 1 Tablets—hydroclilo rothiazide, reserpine... 

CarrelJ, RW. and Travis, J. (1985). Alpha-1-antitrypsin and the serpins variation and countervariation. Trends Biochem. Sci. 10, 20-24. 

Cl-Inh belongs to a superfamily of serine protease inhibitors (serpins) and is a major inhibitor of F-XIIa and kallikrein. It is also an inhibitor of activated complement factors C1 q, C1 r, and C1 s. C1 -Inh thus regulates the activation of two important plasma cascade systems. Proteases induce a conformational change in the plasma protein a2-M, which results in entrapment of the protease into the a2-M cage (B4). In vivo, a2-M acts as a second inhibitor of kallikrein. 

Heparin cofactor II, when activated by binding to glycosaminoglycans (dermatan sulfate, heparins, and heparin), inhibits thrombin (24). The 43-kDa serpin, proteinase nexin 1, possesses 30% sequence homology with ATIII and can be activated by binding to heparin to inhibit several serine proteinases including thrombin (25). Proteinase nexin 2 is found within the platelet a-granule and is released when platelets are activated (26). It is able to inhibit factor XIa. 

Ziady AG, Kelley TJ, Milliken E, Ferkol T, Davis PB (2002) Functional evidence of CFTR gene transfer in nasal epithelium of cystic fibrosis mice in vivo following luminal application of DNA complexes targeted to the serpin-enzyme complex receptor. Mol Ther 5 413-419... 

Beck, B.L., D.C. Henjum, K. Antonijczuk, O. Zaharia, G. Korza, J. Ozols, S.M. Hopfer, A.M. Barber, and F.W. Sunderman, Jr. 1992. pNiXa, a Ni2+-binding protein in Xenopus oocytes and embryos, shows identity to Ep45, an estrogen-regulated hepatic serpin. Res. Comm. Chem. Pathol. Pharmacol. 77 3-16. 

Haspel, J., F.W. Sunderman Jr., S.M. Hopfer, D.C. Henjum, PW. Brandt-Rauf, I.B. Weinstein, S. Nishimura, Z. Yamaizumi, and M.R. Pincus. 1993. A nickel-binding serpin, pNiXa, induces maturation oiXenopus oocytes and shows synergism with oncogenic ras-p21 protein. Res. Comm. Chem. Pathol. Pharmacol. 79 131-140. 

Sunderman, F.W., Jr., A.H. Varghese, O.S. Kroftova, S. Grbac-Ivankovic, J. Kotyza, A.K. Datta, M. Davis, W. Bal, and K.S. Kasprzak. 1996. Characterization of Pnixa, a serpin of Xenopus laevis oocytes and embryos, and its histidine-rich, Ni(II)-binding domain. Molec. Reprod. Develop. 44 507-524. 

Z2. Zou, Z., Anisowicz, A., Hendrix, M., Thor, A., Neveu, M., Sheng, S., Rafidi, K., Seftor, E., and Sager, R., Maspin A serpin with tumor-suppressing activity in human mammary epithelial cells. Science 263, 526-529 (1994). 

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