The human α2-plasmin inhibitor: functional characterization of the unique plasmin(ogen)-binding region

Gerber, Simon; Lejon, Sofia; Locher, Miriam A.; Schaller, Johann

doi:10.1007/s00018-010-0264-3

Cited by 7 publications

(9 citation statements)

References 59 publications

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“…Our findings, which support an involvement of the Lys binding sites of the kringle domains of plasmin(ogen) in the attachment of this host molecule to FBA-tb (Fig. 4B), and the fact that the same domains are known to mediate ␣ 2 -antiplasmin/plasmin interactions (59) suggest that the inhibition of plasmin regulation by ␣ 2 -antiplasmin in the presence of FBA-tb results from a competitive mechanism between the two proteins for the same binding sites on plasmin.…”

Section: Fba-tb Is Expressed During Host Infection-to Assess Fba-tbsupporting

confidence: 82%

Glycolytic and Non-glycolytic Functions of Mycobacterium tuberculosis Fructose-1,6-bisphosphate Aldolase, an Essential Enzyme Produced by Replicating and Non-replicating Bacilli

Santangelo

Gest

Guerin

et al. 2011

Journal of Biological Chemistry

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Background: New drugs active against persistent Mycobacterium tuberculosis are needed. Results: The fructose-1,6-bisphosphate aldolase (FBA-tb) is essential for growth of M. tuberculosis, is expressed by replicating and non-replicating bacilli, and displays plasminogen binding activity. Conclusion: FBA-tb is an essential TB enzyme that might also play a role in host/pathogen interactions. Significance: FBA-tb shows potential as a novel anti-TB therapeutic target.

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Section: Fba-tb Is Expressed During Host Infection-to Assess Fba-tbsupporting

confidence: 82%

Glycolytic and Non-glycolytic Functions of Mycobacterium tuberculosis Fructose-1,6-bisphosphate Aldolase, an Essential Enzyme Produced by Replicating and Non-replicating Bacilli

Santangelo

Gest

Guerin

et al. 2011

Journal of Biological Chemistry

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“…We showed that all conserved Lys residues (Lys-427, Lys-434, Lys-441, Lys-448, and Lys-464) play a role in the interaction with kringle domains of plasmin, with Lys-464 being the main initiator, followed by Lys-448, which corresponds with previously published data (6,10). Individually, the internal Lys residues appear to have a minor function in the interaction with plasmin.…”

Section: Discussionsupporting

confidence: 70%

“…In further experiments, Gerber et al (10) examined the affinity of the recombinant plasmin kringle domains (K1, K1-3, K4, and K4-5). They demonstrated that progressive mutations of lysine residues within the ␣ 2 -antiplasmin C terminus decreased the affinity for K1-3, although the greatest contribution to binding was attributable to Lys-464 and Lys-448.…”

Section: Discussionmentioning

confidence: 99%

“…Frank et al (6) and Gerber et al (10) studied the binding of kringle domains to C-terminal peptide containing Lys-to-Ala mutations. They showed that the C-terminal lysine (Lys-464) was the most important contributor to binding affinity for plasmin kringle domains (6,10). However, kinetic inhibitory studies by Wang et al (11) indicated that Lys-448 in full-length ␣ 2 -antiplasmin was most important in the interaction with plasmin.…”

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confidence: 99%

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Contribution of Conserved Lysine Residues in the α2-Antiplasmin C Terminus to Plasmin Binding and Inhibition

Sofian

Law

et al. 2011

Journal of Biological Chemistry

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␣ 2 -Antiplasmin is the physiological inhibitor of plasmin and is unique in the serpin family due to N-and C-terminal extensions beyond its core domain. The C-terminal extension comprises 55 amino acids from Asn-410 to Lys-464, and the lysine residues (Lys-418, Lys-427, Lys-434, Lys-441, Lys-448, and Lys-464) within this region are important in mediating the initial interaction with kringle domains of plasmin. To understand the role of lysine residues within the C terminus of ␣ 2 -antiplasmin, we systematically and sequentially mutated the C-terminal lysines, studied the effects on the rate of plasmin inhibition, and measured the binding affinity for plasmin via surface plasmon resonance. We determined that the C-terminal lysine (Lys-464) is individually most important in initiating binding to plasmin. Using two independent methods, we also showed that the conserved internal lysine residues play a major role mediating binding of the C terminus of ␣ 2 -antiplasmin to kringle domains of plasmin and in accelerating the rate of interaction between ␣ 2 -antiplasmin and plasmin. When the C terminus of ␣ 2 -antiplasmin was removed, the binding affinity for active siteblocked plasmin remained high, suggesting additional exosite interactions between the serpin core and plasmin.

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“…87,88 Subsequent peptide studies indicated that the a2AP C terminus is flexible, with the most important role for K 464 in the binding of the C terminus to isolated plasminogen kringles, whereas the internal K residues may strengthen this binding in a sequential zipper-like way. 23,89 However, using recombinant intact a2AP, Wang et al 90,91 showed that K…”

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confidence: 99%

Natural heterogeneity of α2-antiplasmin: functional and clinical consequences

Abdul

Leebeek

Rijken

et al. 2016

Blood

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Human a2-antiplasmin (a2AP, also called a2-plasmin inhibitor) is the main physiological inhibitor of the fibrinolytic enzyme plasmin. a2AP inhibits plasmin on the fibrin clot or in the circulation by forming plasmin-antiplasmin complexes. Severely reduced a2AP levels in hereditary a2AP deficiency may lead to bleeding symptoms, whereas increased a2AP levels have been associated with increased thrombotic risk. a2AP is a very heterogeneous protein. In the circulation, a2AP undergoes both amino terminal (N-terminal) and carboxyl terminal (C-terminal) proteolytic modifications that significantly modify its activities. About 70% of a2AP is cleaved at the N terminus by antiplasmin-cleaving enzyme (or soluble fibroblast activation protein), resulting in a 12-amino-acid residue shorter form. The glutamine residue that serves as a substrate for activated factor XIII becomes more efficient after removal of the N terminus, leading to faster crosslinking of a2AP to fibrin and consequently prolonged clot lysis. In approximately 35% of circulating a2AP, the C terminus is absent. This C terminus contains the binding site for plasmin(ogen), the key component necessary for the rapid and efficient inhibitory mechanism of a2AP. Without its C terminus, a2AP can no longer bind to the lysine binding sites of plasmin(ogen) and is only a kinetically slow plasmin inhibitor. Thus, proteolytic modifications of the N and C termini of a2AP constitute major regulatory mechanisms for the inhibitory function of the protein and may therefore have clinical consequences. This review presents recent findings regarding the main aspects of the natural heterogeneity of a2AP with particular focus on the functional and possible clinical implications. (Blood. 2016; 127(5):538-545) Introduction a2-antiplasmin (a2AP, also called a2-plasmin inhibitor) is a key player in the fibrinolytic system (Figure 1). The fibrinolytic system is crucial for dissolving fibrin clots, facilitating tissue repair, and preventing clots from occluding vessels.1 Recent clinical studies have shown that reduced fibrinolysis (eg, due to an increase in a2AP level) is associated with an increase in both venous and arterial thrombotic risk. 2In contrast, an increase in fibrinolysis due to a2AP deficiency is associated with hemophilia-like bleeding symptoms, which typically occur after initial hemostasis as a result of the premature dissolution of fibrin. The phenotype of a2AP deficiency is heterogeneous. Complete congenital a2AP deficiency leads to severe bleeding with hemophilialike bleeding symptoms such as joint bleeding, whereas heterozygous a2AP-deficient patients typically have mild or no bleeding symptoms. 3,4 In addition, acquired a2AP deficiency may also occur in liver disease 5 and amyloidosis 6 or during fibrinolytic therapy. 7The main enzyme of the fibrinolytic system is the serine protease plasmin, which is predominantly responsible for the degradation of fibrin into rapidly cleared soluble fibrin degradation products (Figure 1). The inactive proenzyme plasminogen ca...

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The human α2-plasmin inhibitor: functional characterization of the unique plasmin(ogen)-binding region

Cited by 7 publications

References 59 publications

Glycolytic and Non-glycolytic Functions of Mycobacterium tuberculosis Fructose-1,6-bisphosphate Aldolase, an Essential Enzyme Produced by Replicating and Non-replicating Bacilli

Glycolytic and Non-glycolytic Functions of Mycobacterium tuberculosis Fructose-1,6-bisphosphate Aldolase, an Essential Enzyme Produced by Replicating and Non-replicating Bacilli

Contribution of Conserved Lysine Residues in the α2-Antiplasmin C Terminus to Plasmin Binding and Inhibition

Natural heterogeneity of α2-antiplasmin: functional and clinical consequences

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