Substoichiometric molecular control and amplification of the initiation and nature of amyloid fibril formation: lessons from and for blood clotting

Abstract

The chief and largely terminal element of normal blood clotting is considered to involve the polymerisation of the mainly α-helical fibrinogen to fibrin, with a binding mechanism involving ‘knobs and holes’ but with otherwise littl change in protein secondary structure. We recognise, however, that extremely unusual mutations, or mechanical stressing, can cause fibrinogen to adopt a conformation containing extensive β-sheets. Similarly, prions can change morphology from a largely alpha-helical to a largely β-sheet conformation, and the latter catalyses both the transition and the self-organising polymerisation of the β-sheet structures. Many other proteins can do this, where it is known as amyloidogenesis. When fibrin is formed in samples from patients harbouring different diseases it can have widely varying diameters and morphologies. We here develop the idea, and summarise the evidence, that in many cases the anomalous fibrin fibre formation seen in such diseases actually amounts to amyloidogenesis. In particular, fibrin can interact withthe amyloid-β (Aβ) protein that is misfolded in Alzheimer's disease. Seeing these unusual fibrin morphologies as true amyloids explains a great deal about fibrin(ogen) biology that was previously opaque, and provides novel strategies for treating such coagulopathies. The literature on blood clotting can usefully both inform and be informed by that on prions and on the many other widely recognised (β)-amyloid proteins.“Novel but physiologically important factors that affect fibrinolysis have seldom been discovered and characterized in recent years” [1]

Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide

“…However, this is not true for amyloid fibre formation [ 56 ] nor in the case of the autocatalytic conversion of prion protein conformations [ 57 , 58 ]. At present, the exact mechanisms of action of these small amounts of LPS are not known, although it is indeed simplest to recognize fibrinogen polymerization as a cascade effect, much as occurs for amyloid and prion proteins whose initial conformation is not in fact that of their lowest free energy [ 59 ]. Specifically [ 60 ], the ‘normal’ conformational macrostate of such proteins is not in fact that of the lowest free energy, and its transition to the energetically more favourable ‘rogue’ state is thermodynamically favourable but under kinetic control, normally (in terms of transition state theory) with a very high energy barrier Δ G † of maybe 36–38 kcal mol −1 [ 60 ].…”

A Dormant Microbial Component in the Development of Preeclampsia

“…We recently showed that LPS can potently induce amyloid formation in fibrin (258, 259, 1084, 1085). Thus, in addition, we note the increasing recognition that amyloid proteins themselves, that may occur as a result of coagulopathies, are themselves both inflammatory [e.g., Ref.…”

Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability

“…In a recent development, 232 , 255 , 256 we have shown that the fibrin dense-matted deposits of the type shown in Figure 4(b) can be generated by tiny amounts of LPS, and that they are actually β-amyloid in nature. This has significant implication more generally, 257 including diseases such as sepsis 258 and pre-eclampsia. 259 Amyloid fibrils of various kinds are widely recognized as inflammatory and cytotoxic (e.g.…”