Antithrombin‐TRI (Ala 382 to Thr) causing severe thromboembolic tendency undergoes the S‐to‐R transition and is associated with a plasma‐inactive high‐molecular‐weight complex of aggregated antithrombin

Lindo, Vivian; Kakkar, Vijay V.; Learmonth, Michèle; Melissari, E.; Zappacosta, Francesca; Panico, Maria; Morris, Howard R.

doi:10.1111/j.1365-2141.1995.tb08368.x

Cited by 22 publications

(17 citation statements)

References 52 publications

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“…The measured mass value was slightly larger than predicted for Ss␤gly (M r ϭ 56,690.7), suggesting the occurrence of post-translational modifications. The protein was then submitted to a detailed structural investigation, by employing the ES-mapping strategy developed for the analysis of medium/large-sized proteins (15,40). An aliquot of Ss␤gly was digested with CNBr, and the resulting peptide mixture was fractionated by HPLC.…”

Section: Determination Of the Molecular Mass Of ␤-Glycosidase By Fergmentioning

confidence: 99%

Thermal Stability and Aggregation of Sulfolobus solfataricus β-Glycosidase Are Dependent upon the N-∈-Methylation of Specific Lysyl Residues

Febbraio

Andolfo

Tanfani

et al. 2004

Journal of Biological Chemistry

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Methylation in vivo is a post-translational modification observed in several organisms belonging to eucarya, bacteria, and archaea. Although important implications of this modification have been demonstrated in several eucaryotes, its biological role in hyperthermophilic archaea is far from being understood. The aim of this work is to clarify some effects of methylation on the properties of ␤-glycosidase from Sulfolobus solfataricus, by a structural comparison between the native, methylated protein and its unmethylated counterpart, recombinantly expressed in Escherichia coli. Analysis by Fourier transform infrared spectroscopy indicated similar secondary structure contents for the two forms of the protein. However, the study of temperature perturbation by Fourier transform infrared spectroscopy and turbidimetry evidenced denaturation and aggregation events more pronounced in recombinant than in native ␤-glycosidase. Red Nile fluorescence analysis revealed significant differences of surface hydrophobicity between the two forms of the protein. Unlike the native enzyme, which dissociated into SDS-resistant dimers upon exposure to the detergent, the recombinant enzyme partially dissociated into monomers. By electrospray mapping, the methylation sites of the native protein were identified. A computational analysis of ␤-glycosidase three-dimensional structure and comparisons with other proteins from S. solfataricus revealed analogies in the localization of methylation sites in terms of secondary structural elements and overall topology. These observations suggest a role for the methylation of lysyl residues, located in selected domains, in the thermal stabilization of ␤-glycosidase from S. solfataricus.

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Section: Determination Of the Molecular Mass Of ␤-Glycosidase By Fergmentioning

confidence: 99%

Thermal Stability and Aggregation of Sulfolobus solfataricus β-Glycosidase Are Dependent upon the N-∈-Methylation of Specific Lysyl Residues

Febbraio

Andolfo

Tanfani

et al. 2004

Journal of Biological Chemistry

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“…Serpins are also able to link their reactive loop to a ␤-sheet of another molecule to form loop-sheet polymers, one form of which (18) has recently been crystallized (19,20). These polymers are of considerable importance because they underlie the deficiency of ␣ 1 -antitrypsin (3, 21-25), antithrombin (13,26,27), ␣ 1 -antichymotrypsin (28), and C1-inhibitor (29, 30) in association with liver cirrhosis, thromboembolism, emphysema, and angioedema, respectively. The process also underlies a novel early onset dementia characterized by inclusion bodies of neuroserpin polymers (31).…”

Section: Plasminogen Activator Inhibitor Type 1 (Pai-1)mentioning

confidence: 99%

Polymerization of Plasminogen Activator Inhibitor-1

Zhou¹,

Faint²,

Charlton³

et al. 2001

Journal of Biological Chemistry

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The activity of the serine proteinase inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1) is controlled by the intramolecular incorporation of the reactive loop into ␤-sheet A with the generation of an inactive latent species. Other members of the serpin superfamily can be pathologically inactivated by intermolecular linkage between the reactive loop of one molecule and ␤-sheet A of a second to form chains of polymers associated with diverse diseases. It has long been believed that PAI-1 is unique among active serpins in that it does not form polymers. We show here that recombinant native and latent PAI-1 spontaneously form polymers in vitro at low pH although with distinctly different electrophoretic patterns of polymerization. The polymers of both the native and latent species differ from the typical loop-Asheet polymers of other serpins in that they readily dissociate back to their original monomeric form. The findings with PAI-1 are compatible with different mechanisms of linkage, each involving ␤-strand addition of the reactive loop to s7A in native PAI-1 and to s1C in latent PAI-1. Glycosylated native and latent PAI-1 can also form polymers under similar conditions, which may be of in vivo importance in the low pH environment of the platelet. Plasminogen activator inhibitor type 1 (PAI-1)1 is a member of the serine proteinase inhibitor or serpin superfamily (1, 2). Serpins play an important role in the control of proteinases involved in blood coagulation, complement activation, and inflammation and are distinguished functionally from other types of protein inhibitors by their ability to form SDS stable complexes with target proteinases. Crystal structures have shown that members of the family share a highly conserved tertiary fold consisting of three large ␤-sheets surrounded by nine ␣-helices. This scaffold presents the reactive loop as a pseudosubstrate that binds to and inhibits the target proteinase (3). The target proteinases of PAI-1 are urokinase-type plasminogen activator and tissue-type plasminogen activator (tPA) (4) and as such it is an important modulator of events of extracellular proteolysis in fibrinolysis and in the turnover of extracellular matrix (5).One of the most striking features of serpins is their ability to undergo a dramatic conformational rearrangement with the N-terminal portion of the reactive loop inserting into ␤-sheet A (6). This transition with cleavage of the loop is central to the formation of a stable inhibitory complex (7-10), but it can also occur spontaneously in vivo, without cleavage of the loop, to form an inactive latent conformation (11-14). Moreover, antithrombin and ␣ 1 -antitrypsin can be induced to adopt a latent conformation by heating in stabilizing concentrations of sodium citrate (15-17). Serpins are also able to link their reactive loop to a ␤-sheet of another molecule to form loop-sheet polymers, one form of which (18) has recently been crystallized (19,20). These polymers are of considerable importance because they underlie the deficiency of ␣...

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“…17), similarly form loop-sheet polymers in vivo (18,19). Polymerization also accounts for the mild deficiency of the common S variant ( 264 Glu→Val) of α 1 -antitrypsin (20) and has been described in mutants of other members of the serpin family in association with angioedema (21,22) and thrombosis (23,24). Mutants that favor polymerization cluster in mobile structural domains of the serpins, particularly in the shutter domain that underlies the A β-pleated sheet (25).…”

Section: Introductionmentioning

confidence: 97%

Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis

Mahadeva¹,

Chang²,

Dafforn³

et al. 1999

J. Clin. Invest.

183

115

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The association between Z α 1 -antitrypsin deficiency and juvenile cirrhosis is well-recognized, and there is now convincing evidence that the hepatic inclusions are the result of entangled polymers of mutant Z α 1 -antitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S α 1 -antitrypsin, which is found in up to 28% of southern Europeans. The S variant is known to have an increased susceptibility to polymerization, although this is marginal compared with the more conformationally unstable Z variant. There has been speculation that the two may interact to produce cirrhosis, but this has never been demonstrated experimentally. This hypothesis was raised again by the observation reported here of a mixed heterozygote for Z α 1 -antitrypsin and another conformationally unstable variant (I α 1 -antitrypsin; 39 Arg→Cys) identified in a 34-year-old man with cirrhosis related to α 1 -antitrypsin deficiency. The conformational stability of the I variant has been characterized, and we have used fluorescence resonance energy transfer to demonstrate the formation of heteropolymers between S and Z α 1 -antitrypsin. Taken together, these results indicate that not only may mixed variants form heteropolymers, but that this can causally lead to the development of cirrhosis.

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Antithrombin‐TRI (Ala 382 to Thr) causing severe thromboembolic tendency undergoes the S‐to‐R transition and is associated with a plasma‐inactive high‐molecular‐weight complex of aggregated antithrombin

Cited by 22 publications

References 52 publications

Thermal Stability and Aggregation of Sulfolobus solfataricus β-Glycosidase Are Dependent upon the N-∈-Methylation of Specific Lysyl Residues

Thermal Stability and Aggregation of Sulfolobus solfataricus β-Glycosidase Are Dependent upon the N-∈-Methylation of Specific Lysyl Residues

Polymerization of Plasminogen Activator Inhibitor-1

Heteropolymerization of S, I, and Z α1-antitrypsin and liver cirrhosis

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