52
7.1 Inhibitory Role as a Powerful Serpin
C1-INH is a plasma protein that is best known for
its starring role as a protease inhibitor. Originally
the molecule was named for its action in suppressing
C1 esterase in the classical pathway of the complement
system (the system that mediates host defense against
pathogens and altered host cells).
28,103
Subsequent
scientific discoveries have determined that C1-INH
also functions as an inhibitor of numerous substrates
besides C1 esterase, rendering the name C1-INH some-
what of a misnomer.
C1-INH belongs to a larger family of plasma proteins that
inhibit proteases by binding covalently to critical serine
residues at their active site.
103-106
These serine protease
inhibitors are collectively called serpins. Other protease
inhibitors in the serpin family include, among others,
alpha1-antitrypsin, alpha2-antiplasmin, heparin cofactor II,
and antithrombin III.
5,6,26,102
Like other serpins, C1-INH has a reactive loop, a bait
sequence at which C1-INH acts as a pseudosubstrate,
attracting and trapping the target protease.
26,102,103,106
This reactive loop determines both the specific-
ity to target proteases and the reaction rate.
104
When
the target protease attaches to the C1-INH molecule
at the reactive loop, the single chain is cleaved, and the
molecule springs closed like a mousetrap, forming a
covalent bond between the enzyme and the C1-INH
molecule at the reactive loop site. Thus, a fourth beta-
sheet is formed (Figure 26).
102
This conformational change
(and the ability to form covalent bonds with the target pro-
teases) is unique to serpins, because most other enzyme
inhibitors function with a simple lock-and-key mechanism.
As a serpin, C1-INH inhibits 4 enzyme cascades of the
human body: the complement system, the KKS, the fibrino-
lytic system, and the coagulation cascade.
102
7.11 C1-INH is the Primary Inhibitor of
the Complement System
The complement system is part of the immune system. It
consists of 3 activation pathways that lead to the gene-
ration of chemoattractants, activation of leukocytes, and
formation of a “membrane attack complex” which can lyse
cells. These activation pathways include the:
•
Classical complement pathway
•
Alternative complement pathway
•
Mannose-binding lectin pathway.
Overactivation of the complement system can be po-
tentially damaging to host tissue, so its activation must
be tightly regulated. C1-INH is the primary control
protein that regulates the classical and lectin pathways
in complement activation, and hence the inflammatory
response.
5,104
In the classical pathway, C1-INH is the only inhibitor
of C1r and C1s – components of the C1 molecule that
cleave and activate C2 and C4.
5-8,12,24,102,103,105
Thus,
C1-INH blocks the consumption of C4. As discussed in
chapter 2, low C4 levels are of diagnostic significance in
HAE.
C1-INH also inhibits the mannose-binding lectin-
associated serine proteases of the lectin pathway, which
are called MASPs (mannose-binding protein-associated
serine proteases) and are functionally analogous to C1r
and C1s.
5,28,102-105
Although alpha2-macroglobulin can also
inhibit MASP-2, C1-INH is likely its primary inhibitor.
103,105,106
By blocking the MASPs, C1-INH blocks the cleavage and
activation of C2 and C4 in this pathway as well.
105,106
C1-INH can also inhibit the alternative pathway. However,
the mechanism of action in this third pathway is not as a
serpin. Instead, the C1-INH molecule reversibly binds to
C3b.
28,103,106
Therefore, C1-INH downregulates all 3 pathways of the
complement system: the classical pathway, the lectin
pathway, and the alternative pathway.
