Identification of Respective Lysine Donor and Glutamine Acceptor Sites Involved in Factor XIIIa-catalyzed Fibrin α Chain Cross-linking

Wang, Weixun

doi:10.1074/jbc.m111.297119

Cited by 23 publications

(30 citation statements)

References 48 publications

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“…[17][18][19][20] Five known reactive glutamines in the aC region include Q221 (and/or 223), Q237, Q328, and Q366. 16,[21][22][23] FXIIIa also crosslinks a 2 -antiplasmin (a 2 AP), plasmin activator inhibitor 2 (PAI-2), and fibronectin into the fibrin clot network. [24][25][26][27] FXIII(a) and fibrinogen play additional supporting roles in the presence of red blood cells.…”

Section: Introductionmentioning

confidence: 99%

“…40 Several studies have identified specific crosslinking sites in the aC region responsible for lateral aggregation, but little is known about the individual reactive glutamines and the roles played by the surrounding residues. 17,18,20,22,23,41,42 Antibody studies by Procyk et al identified a FXIIIa binding site within aC (242-424) and then narrowed the site more specifically to aC (389-402). 43 Using recombinant aC (233-425), Smith et al demonstrated that the key contact region for FXIII A 2 9 (thrombin-activated) and A 2 B 2 involves aC (371-425) with E396 playing an important role.…”

Section: Introductionmentioning

confidence: 99%

“…44,45 In close proximity to this FXIII binding region, aC (233-425) contains three reactive glutamines (Q237, Q328, and Q366) that each become crosslinked to a selective set of lysines within the fibrin clot network. 17,23 The aim of the current study was to characterize the glutamines within the fibrinogen aC region (233-425) that are known to be crosslinked by FXIIIa under physiological conditions. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry and 2D heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) assays were used to directly monitor FXIIIa-catalyzed reactions between the substrate glutamines in aC (233-425) and a set of lysine mimics.…”

Section: Introductionmentioning

confidence: 99%

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Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

Mouapi

Bell

Smith

et al. 2016

Blood

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Key Points• FXIIIa exhibits a preference for Q237 in crosslinking reactions within fibrinogen aC (233-425) followed by Q328 and Q366.• None of the reactive glutamines in aC 233-425 (Q237, Q328, and Q366) are required to react first before the others can crosslink.Factor XIIIa (FXIIIa) introduces covalent g-glutamyl-«-lysyl crosslinks into the blood clot network. These crosslinks involve both the g and a chains of fibrin. The C-terminal portion of the fibrin a chain extends into the aC region (210-610). Crosslinks within this region help generate a stiffer clot, which is more resistant to fibrinolysis. Fibrinogen aC (233-425) contains a binding site for FXIIIa and three glutamines Q237, Q328, and Q366 that each participate in physiological crosslinking reactions. Although these glutamines were previously identified, their reactivities toward FXIIIa have not been ranked. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry and nuclear magnetic resonance (NMR) methods were thus used to directly characterize these three glutamines and probe for sources of FXIIIa substrate specificity. Glycine ethyl ester (GEE) and ammonium chloride served as replacements for lysine. Mass spectrometry and 2D heteronuclear single quantum coherence NMR revealed that Q237 is rapidly crosslinked first by FXIIIa followed by Q366 and Q328. Both N-GEE could be crosslinked to the three glutamines in aC (233-425) with a similar order of reactivity as observed with the MALDI-TOF mass spectrometry assay. NMR studies using the single aC mutants Q237N, Q328N, and Q366N demonstrated that no glutamine is dependent on another to react first in the series. Moreover, the remaining two glutamines of each mutant were both still reactive. Further characterization of Q237, Q328, and Q366 is important because they are located in a fibrinogen region susceptible to physiological truncations and mutation. The current results suggest that these glutamines play distinct roles in fibrin crosslinking and clot architecture. (Blood. 2016;127(18):2241-2248

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

Mouapi

Bell

Smith

et al. 2016

Blood

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“…The αC reactivity ranking Q237 >> Q366 ≈ Q328 provides new information to help interpret crosslinking pairs reported recently for full length fibrinogen. 82 For that study, the FXIIIa catalyzed crosslinking reactions were followed by trypsin digests and mass spectral analysis. Wang demonstrated that Q237 could be crosslinked to more lysine pairs (αK418, αK508, αK539 αK556 and αK601) than all other reactive glutamines that were probed.…”

Section: 72mentioning

confidence: 99%

“…Wang demonstrated that Q237 could be crosslinked to more lysine pairs (αK418, αK508, αK539 αK556 and αK601) than all other reactive glutamines that were probed. 82 The high reactivity documented for Q237 suggests that this amino acid is well positioned to crosslink a variety of reactive lysines. Unlike Q237, Wang reported that αC Q366 only crosslinks to K539.…”

Section: 72mentioning

confidence: 99%

Characterizing reactive glutamines in fibrinogen and elucidating factor XIII substrate specificity.

Mouapi¹

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Fibrinogen αC domain: Its importance in physiopathology

Mirshahi

Varin

et al. 2019

Research and Practice in Thrombosis and Haemostasis

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Essentials The C‐terminal domain of the fibrinogen α chain (αC domain) is implicated in different severe diseases via clotting abnormalities or amyloid deposits. Certain anomalies of the fibrinogen molecule lead to amyloid deposits in the kidney, inducing renal insufficiency. In contrast, in Alzheimer's disease, fibrinogen is normal, but due to an inflammatory process, fibrinogen crosses into the brain and interacts with Aβ, leading to formation of pathological deposits. Abstract Fibrinogen, involved in coagulation, is a soluble protein composed of two sets of disulfide‐bridged Aα, Bβ, and γ‐chains. In this review, we present the clinical implications of the αC domain of the molecule in Alzheimer's disease, hereditary renal amyloidosis and a number of thrombotic and hemorrhagic disorders. In Alzheimer's disease, amyloid beta peptide (Aβ) is increased and binds to the αC domain of normal fibrinogen, triggering increased fibrin(ogen) deposition in patients’ brain parenchyma. In hereditary renal amyloidosis, fibrinogen is abnormal, with mutations located in the fibrinogen αC domain. The mutant αC domain derived from fibrinogen degradation folds incorrectly so that, in time, aggregates form, leading to amyloid deposits in the kidneys. In these patients, no thrombotic tendency has been observed. Abnormal fibrinogens with either a point mutation in the αC domain or a frameshift mutation resulting in absence of a part of the αC domain are often associated with either thrombotic events or bleeding. Mutation of an amino acid into cysteine (as in fibrinogens Dusart and Caracas V) or a frameshift mutation yielding an unpaired cysteine in the αC domain is often responsible for thrombotic events. Covalent binding of albumin to the unpaired cysteine via a disulphide bridge leads to decreased accessibility to the fibrinolytic enzymes, hence formation of poorly degradable fibrin clots, which explains the high incidence of thrombosis. In contrast, anomalies due to a frameshift mutation in the αC connector of the molecule, provoking deletion of a great part of the αC domain, are associated with bleeding.

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Identification of Respective Lysine Donor and Glutamine Acceptor Sites Involved in Factor XIIIa-catalyzed Fibrin α Chain Cross-linking

Cited by 23 publications

References 48 publications

Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

Ranking reactive glutamines in the fibrinogen αC region that are targeted by blood coagulant factor XIII

Characterizing reactive glutamines in fibrinogen and elucidating factor XIII substrate specificity.

Fibrinogen αC domain: Its importance in physiopathology

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