Mammalian Functional Amyloid - The Functional Fold: Amyloid Structures in Nature - page 148

9.1 Amyloid as a Structural and Regulatory

Component of Haemostasis

Regulation of blood clot formation and removal is a critical function
of the human haemostatic system. Blood clotting is an important
part of response to physical injury. Conversely, inappropriate
clot formation can lead to thrombus formation and blood vessel
blockage. Clot formation and removal is controlled by a series of
proteolytic cascades. Clot formation is induced by activation of the
Factor XII protease that initiates a proteolytic cascade resulting in
the cleavage of fibrinogen to produce fibrin. Fibrin then polymerizes
to form a fibrous network that is a major component of blood
clots. Clot dissolution and degradation of polymerized fibrin is
accomplished by the protease plasmin, which is generated from
plasminogen by tissue-type plasminogen activator (tPA). , tPA

and plasminogen are recruited to fibrin clots, thereby increasing
their effective concentration and leading to plasmin formation and,
ultimately, fibrin degradation.
Recent studies suggest that fibrin fibres may comprise, at least
in part, an amyloid-like structure. Fibrin fibres have a high

In vivo

β

-sheet

1 2

content and can be stained with Congo red under certain conditions.

β

Raman spectroscopy studies show that fibrin acquires more -sheet

structure upon assembly into fibres, although polarization studies
suggest that

β

3

-sheets are oriented parallel to the fibrin fibre axis.

Additionally, fibrin-derived peptides assemble into amyloid fibres
as shown by circular dichroism, X-ray fibre diffraction, and Congo
red staining.

2

Despite these suggestive data, the exact structure
of fibrin fibres as well as the role that cross-

-sheet motifs play
in the assembly and structural integrity of clots remains largely
unknown. One possibility is that fibrin fibres contain amyloid-like
microdomains for structural or regulatory purposes.
Intriguingly, experiments suggest that such amyloid structures
in fibrin fibres could be important in regulating the degradation of
clots. Fibrin clots are degraded by the plasmin protease, which is
generated from the zymogen plasminogen by tPA. Plasmin generation
by tPA is regulated by the recruitment of both plasminogen and tPA
to fibrin clots; the increased effective concentration, along with tPA
activation, leads to plasmin formation. The amyloid motifs contained
within fibrin may be responsible for the stimulation of tPA-mediated
plasminogen processing. In fact, amyloid fibres derived from a

β