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Thrombin a-chain: activation remnant or allosteric effector?

Carter IS, Vanden Hoek AL, Pryzdial EL, Macgillivray RT - Thrombosis (2010)

Bottom Line: This paper summarizes the current data on the prothrombin catalytic domain A-chain region and the subsequent thrombin A-chain.Attention is given to biochemical characterization of naturally occurring prothrombin A-chain mutations and alanine scanning mutants in this region.While originally considered to be simply an activation remnant with little physiologic function, the thrombin A-chain is now thought to play a role as an allosteric effector in enzymatic reactions and may also be a structural scaffold to stabilize the protease domain.

View Article: PubMed Central - PubMed

Affiliation: Centre for Blood Research, University of British Columbia (UBC), Vancouver, BC, Canada V6T 1Z3.

ABSTRACT
Although prothrombin is one of the most widely studied enzymes in biology, the role of the thrombin A-chain has been neglected in comparison to the other domains. This paper summarizes the current data on the prothrombin catalytic domain A-chain region and the subsequent thrombin A-chain. Attention is given to biochemical characterization of naturally occurring prothrombin A-chain mutations and alanine scanning mutants in this region. While originally considered to be simply an activation remnant with little physiologic function, the thrombin A-chain is now thought to play a role as an allosteric effector in enzymatic reactions and may also be a structural scaffold to stabilize the protease domain.

No MeSH data available.


Related in: MedlinePlus

Activation of thrombin by the prothrombinase complex (reviewed in [4]). Prothrombin is colored by domain in this schematic, highlighting the A-chain (pink) and B-chain (yellow). The gamma carboxylated Gla residues are noted by (Y) at the N terminus of prothrombin, the carbohydrate attachment sites in kringle 1 (K1) and the B domain are noted by the shaded star, and the disulfide bridges are shown. Factor Xa initially cleaves Prothrombin (a) at Arg 320 to produce meizothrombin (d), followed by cleavage at Arg 271 to release fragment 1.2 from nascent thrombin (e). Thrombin then undergoes intermolecular autolysis to cleave the Arg 285/Thr 286 bond (f), liberating the A13 peptide (pale pink) to generate α-thrombin. Experimental constructs used in biochemical studies of the thrombin A-chain include prethrombin-1, which lacks fragment 1 (b) and prethrombin-2 (c).
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fig1: Activation of thrombin by the prothrombinase complex (reviewed in [4]). Prothrombin is colored by domain in this schematic, highlighting the A-chain (pink) and B-chain (yellow). The gamma carboxylated Gla residues are noted by (Y) at the N terminus of prothrombin, the carbohydrate attachment sites in kringle 1 (K1) and the B domain are noted by the shaded star, and the disulfide bridges are shown. Factor Xa initially cleaves Prothrombin (a) at Arg 320 to produce meizothrombin (d), followed by cleavage at Arg 271 to release fragment 1.2 from nascent thrombin (e). Thrombin then undergoes intermolecular autolysis to cleave the Arg 285/Thr 286 bond (f), liberating the A13 peptide (pale pink) to generate α-thrombin. Experimental constructs used in biochemical studies of the thrombin A-chain include prethrombin-1, which lacks fragment 1 (b) and prethrombin-2 (c).

Mentions: Prothrombin is a single chain glycoprotein of Mr 72,000 that circulates in plasma at a concentration of 100–200 μg/mL. As shown in Figure 1, prothrombin consists of four structural domains: the Gla domain, a region containing 10 γ-carboxylated glutamic acid residues which mediate pro thrombin binding to procoagulant phospholipid surfaces; two kringle domains, which are thought to be involved in protein-protein interactions; and lastly the trypsin-like serine protease domain, which contains the enzyme active site. Disulfide bonds and cleavage sites are also shown in Figure 1. Prothrombin also has three N-linked carbohydrate chains at residues Asn78, Asn100 (located in the kringle domain 1), and Asn373 (present in the serine protease domain) [1].


Thrombin a-chain: activation remnant or allosteric effector?

Carter IS, Vanden Hoek AL, Pryzdial EL, Macgillivray RT - Thrombosis (2010)

Activation of thrombin by the prothrombinase complex (reviewed in [4]). Prothrombin is colored by domain in this schematic, highlighting the A-chain (pink) and B-chain (yellow). The gamma carboxylated Gla residues are noted by (Y) at the N terminus of prothrombin, the carbohydrate attachment sites in kringle 1 (K1) and the B domain are noted by the shaded star, and the disulfide bridges are shown. Factor Xa initially cleaves Prothrombin (a) at Arg 320 to produce meizothrombin (d), followed by cleavage at Arg 271 to release fragment 1.2 from nascent thrombin (e). Thrombin then undergoes intermolecular autolysis to cleave the Arg 285/Thr 286 bond (f), liberating the A13 peptide (pale pink) to generate α-thrombin. Experimental constructs used in biochemical studies of the thrombin A-chain include prethrombin-1, which lacks fragment 1 (b) and prethrombin-2 (c).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3211113&req=5

fig1: Activation of thrombin by the prothrombinase complex (reviewed in [4]). Prothrombin is colored by domain in this schematic, highlighting the A-chain (pink) and B-chain (yellow). The gamma carboxylated Gla residues are noted by (Y) at the N terminus of prothrombin, the carbohydrate attachment sites in kringle 1 (K1) and the B domain are noted by the shaded star, and the disulfide bridges are shown. Factor Xa initially cleaves Prothrombin (a) at Arg 320 to produce meizothrombin (d), followed by cleavage at Arg 271 to release fragment 1.2 from nascent thrombin (e). Thrombin then undergoes intermolecular autolysis to cleave the Arg 285/Thr 286 bond (f), liberating the A13 peptide (pale pink) to generate α-thrombin. Experimental constructs used in biochemical studies of the thrombin A-chain include prethrombin-1, which lacks fragment 1 (b) and prethrombin-2 (c).
Mentions: Prothrombin is a single chain glycoprotein of Mr 72,000 that circulates in plasma at a concentration of 100–200 μg/mL. As shown in Figure 1, prothrombin consists of four structural domains: the Gla domain, a region containing 10 γ-carboxylated glutamic acid residues which mediate pro thrombin binding to procoagulant phospholipid surfaces; two kringle domains, which are thought to be involved in protein-protein interactions; and lastly the trypsin-like serine protease domain, which contains the enzyme active site. Disulfide bonds and cleavage sites are also shown in Figure 1. Prothrombin also has three N-linked carbohydrate chains at residues Asn78, Asn100 (located in the kringle domain 1), and Asn373 (present in the serine protease domain) [1].

Bottom Line: This paper summarizes the current data on the prothrombin catalytic domain A-chain region and the subsequent thrombin A-chain.Attention is given to biochemical characterization of naturally occurring prothrombin A-chain mutations and alanine scanning mutants in this region.While originally considered to be simply an activation remnant with little physiologic function, the thrombin A-chain is now thought to play a role as an allosteric effector in enzymatic reactions and may also be a structural scaffold to stabilize the protease domain.

View Article: PubMed Central - PubMed

Affiliation: Centre for Blood Research, University of British Columbia (UBC), Vancouver, BC, Canada V6T 1Z3.

ABSTRACT
Although prothrombin is one of the most widely studied enzymes in biology, the role of the thrombin A-chain has been neglected in comparison to the other domains. This paper summarizes the current data on the prothrombin catalytic domain A-chain region and the subsequent thrombin A-chain. Attention is given to biochemical characterization of naturally occurring prothrombin A-chain mutations and alanine scanning mutants in this region. While originally considered to be simply an activation remnant with little physiologic function, the thrombin A-chain is now thought to play a role as an allosteric effector in enzymatic reactions and may also be a structural scaffold to stabilize the protease domain.

No MeSH data available.


Related in: MedlinePlus