Biomedical Engineering Reference
In-Depth Information
(a)
D
D
E
(b)
6.1
Fibrinogen models based on low-resolution X-ray crystallography
and electron microscopy. (a) Trinodular model consists of a central
globular E domain connected via coiled-coil regions to two outer
globular D domains. The molecule is symmetric about a line
perpendicular to the molecular axis. (b) Octaglobular model as each
D domain is split into two globular domains, a distal
β
C region and a
proximal
γ
C region. The two
α
C regions fold back and form an extra
globular domain near the E domain. The coiled-coil region is interrupted
by a non-helical, plasmin-sensitive domain for degradation. The
approximate location of dodecapeptides and RGD sequences for platelet
binding via integrin receptor, glycoprotein IIb-IIIa, is specifi ed (▲).
2.
A sequential three-step non-covalent assembly.
3 .
Factor
XIIIa-catalyzed
crosslinking
on
adjacent
fi brin molecules
( Fig. 6.2 ).
Native fi brinogen molecule carries a net negative charge which keeps the
molecules apart due to electrostatic repulsion.
10,44
However, in fi brin mono-
mer, its central E domain carries a net positive charge, whereas each outer
D domain still possesses a net negative charge, thus forming the basis for
the non-covalent fi brin assembly through electrostatic interactions.
45-51
The product during initial fi brin assembly is a two-stranded protofi bril
formed by the complementary binding of fi brin monomers arranged at a
half-staggered overlapping structure that corresponds to half of the molecu-
lar length of fi brinogen.
45
Lateral association of different protofi brils leads to
the formation of thick fi brin fi bers.
4,52
Moreover, bending of fi brin strands is
found, suggesting geometric constraints may be important in controlling the
structure of fi brin strands.
53
Eventually, lateral aggregation of fi brin fi bers,
presumably mediated by the αC domain, gives rise to large bundles.
43,44,54
