Packaging zinc, fibrinogen, and factor XIII in platelet α‐granules

Marx, Gerard; Korner, Gil; Mou, Xiaode; Gorodetsky, Raphael

doi:10.1002/jcp.1041560302

Cited by 72 publications

(72 citation statements)

References 49 publications

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“…The zinc-mediated reversible precipitation of A␤ can be compared with the interaction of zinc with fibrin whose solubility state is dependent upon zinc for physiological purposes (47). A␤ is found in platelets (48) where it may colocalize with high concentrations (Ͼ300 M) of zinc as well as the APP (49), fibrinogen, and other coagulation factors (50) in the ␣-secretory granule. Platelet zinc release modulates the propagation of the coagulation cascade through its action on protease activities, such as the effect of zinc at micromolar concentrations in se-lectively enhancing the inhibition of coagulation factor XIa by protease nexin-2/APP (51), probably through binding to the zinc-binding site on the amino terminus of APP (38).…”

Section: Resultsmentioning

confidence: 99%

Zinc-induced Alzheimer's Aβ1–40 Aggregation Is Mediated by Conformational Factors

Huang

Atwood

Moir

et al. 1997

Journal of Biological Chemistry

321

260

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The heterogeneous precipitates of A␤ that accumulate in the brain cortex in Alzheimer's disease possess varying degrees of resistance to resolubilization. We previously found that A␤1-40 is rapidly precipitated in vitro by physiological concentrations of zinc, a neurochemical that is highly abundant in brain compartments where A␤ is most likely to precipitate. We now present evidence that the zinc-induced precipitation of A␤ is mediated by a peptide dimer and favored by conditions that promote ␣-helical and diminish ␤-sheet conformations. The manner in which the synthetic peptide is solubilized was critical to its behavior in vitro. Zincinduced A␤ aggregation was dependent upon the presence of NaCl, was enhanced by ␣-helical-promoting solvents, but was abolished when the peptide stock solution was stored frozen. The A␤ aggregates induced by zinc were reversible by chelation, but could then be reprecipitated by zinc for several cycles, indicating that the peptide's conformation is probably preserved in the zinc-mediated assembly. In contrast, A␤ aggregates induced by low pH (5.5) were not resolubilized by returning the pH milieu to 7.4. The zinc-A␤ interaction exhibits features resembling the gelation process of zinc-mediated fibrin assembly, suggesting that, in events such as clot formation or injury, reversible A␤ assembly could be physiologically purposive. Such a mechanism is contemplated in the early evolution of diffuse plaques in Alzheimer's disease and suggests a possible therapeutic strategy for the resolubilization of some forms of A␤ deposit in the disease.The pathological hallmark of Alzheimer's disease is the abundant accumulation in the brain of A␤, a 39 -43-amino acid peptide, as morphologically heterogeneous deposits in the neuropil (senile plaques) and cerebral blood vessels (congophilic angiopathy) (1, 2). A␤ is a soluble component of cerebrospinal fluid where it is found in concentrations in the low nanomolar range (3-5). Many studies now indicate that synthetic A␤ becomes toxic to cultured neuronal cells when in a specific ␤-sheet conformation that involves incubating the synthetic peptide in a aqueous solution over time periods of days to weeks (6 -14). Whereas the ␤-sheet conformation of the peptide is found in highly insoluble fibrillar amyloid deposits in Alzheimer's disease, a substantial proportion of A␤ precipitates into nonfibrillar deposits that can be resolubilized by extraction into aqueous solvents (15).We have recently reported that A␤ itself specifically and saturably binds zinc, manifesting high affinity binding (K D ϭ 107 nM) with a 1:1 (zinc:A␤) stoichiometry and low affinity binding (K D ϭ 5.2 M) with a 2:1 stoichiometry (16). This binding is probably histidine-mediated since it is abolished by acidic pH (no binding at pH 6). The zinc-binding site was mapped to a stretch of contiguous residues between positions 6 -28 of the A␤ sequence. Occupation of the zinc-binding site, which straddles the lysine 16 position of ␣-secretase cleavage (17, 18), inhibits ␣-secretase type (tryp...

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Section: Resultsmentioning

confidence: 99%

Zinc-induced Alzheimer's Aβ1–40 Aggregation Is Mediated by Conformational Factors

Huang

Atwood

Moir

et al. 1997

Journal of Biological Chemistry

321

260

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“…[51][52][53] HRG binds to FXIIa with incredibly high affinity in the presence of Zn 21 ions, 51 and both are released from platelet a-granules upon activation. 54,55 HRG also associates with DNA and RNA and attenuates nucleic acid-driven activation of FXII. 52 Here, we show for the first time that HRG dampens aFXIIa activity directed toward the fibrinolytic pathway, adding to the complexity of this unusual adapter protein in regulation of hemostatic pathways.…”

Section: Discussionmentioning

confidence: 99%

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Mitchell

Lionikiene

Georgiev

et al. 2016

Blood

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Key Points• PolyP significantly augments the plasminogen activator capacity of FXIIa.• Platelet-bound fibrin acts as a reservoir for plasminogen, FXII(a), and polyP.Activated factor XII (FXIIa) has plasminogen activator capacity but its relative contribution to fibrinolysis is considered marginal compared with urokinase and tissue plasminogen activator. Polyphosphate (polyP) is released from activated platelets and mediates FXII activation. Here, we investigate the contribution of polyP to the plasminogen activator function of aFXIIa. We show that both polyP 70 , of the chain length found in platelets (60-100 mer), and platelet-derived polyP significantly augment the plasminogen activation capacity of aFXIIa. PolyP 70 stimulated the autoactivation of FXII and subsequent plasminogen activation, indicating that once activated, aFXIIa remains bound to polyP 70 . Indeed, complex formation between polyP 70 and aFXIIa provides protection against autodegradation. Plasminogen activation by bFXIIa was minimal and not enhanced by polyP 70 , highlighting the importance of the anion binding site. PolyP 70 did not modulate plasmin activity but stimulated activation of Glu and Lys forms of plasminogen by aFXIIa. Accordingly, polyP 70 was found to bind to FXII, aFXIIa, and plasminogen, but not bFXIIa. Fibrin and polyP 70 acted synergistically to enhance aFXIIa-mediated plasminogen activation. The plasminogen activator activity of the aFXIIa-polyP 70 complex was modulated by C1 inhibitor and histidine-rich glycoprotein, but not plasminogen activator inhibitors 1 and 2. Platelet polyP and FXII were found to colocalize on the activated platelet membrane in a fibrin-dependent manner and decorated fibrin strands extending from platelet aggregates. We show that in the presence of platelet polyP and the downstream substrate fibrin, aFXIIa is a highly efficient and favorable plasminogen activator. Our data are the first to document a profibrinolytic function of platelet polyP. (Blood. 2016;128(24):2834-2845

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“…27 Platelets are reported to store zinc and HRG in their a-granules, and both components are released upon platelet activation. 39,46 In the presence of zinc, the affinity of FXIIa for HRG is heightened by 1000-fold to a K d value of 7.5 pM, 27 which is higher than the affinity of HRG for other ligands. 26 This creates a potential molecular switch that directs HRG to FXIIa.…”

Section: Discussionmentioning

confidence: 99%

Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein

Zhou

Leslie

et al. 2015

Blood

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Packaging zinc, fibrinogen, and factor XIII in platelet α‐granules

Cited by 72 publications

References 49 publications

Zinc-induced Alzheimer's Aβ1–40 Aggregation Is Mediated by Conformational Factors

Zinc-induced Alzheimer's Aβ1–40 Aggregation Is Mediated by Conformational Factors

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein

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