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cOMPLEMENT.ppt
1.
2. Complement
What is “it”? A series of serum
proteins.
How is it recognized? By its ability to mediate
cell lysis. (Review the
fascinating story of its
discovery!)
What does it have to do with IMMUNOLOGY?
3. The overview….
• Complement has
three functions:
– Opsonin
– Chemoattractant
– Membrane Attack
Complex (MAC)
• Complement functions
in two (three?) systems:
– Alternative
– Classical
– Lectin-based
4. The alternative system
• C3 is the principal protein of
concern.
– Exists in high concentrations (1.2
mg ml-1
– Contains an unstable internal
thiolester with slow “spontaneous”
(or serum protease mediated)
cleavage.
• By convention, the smaller product is
designated “a” and the larger “b”
(though there is one exception.)
C3b can bind to bacteria and
enhance phagocytosis.
5. C3b can bind to bacteria and enhance phagocytosis.
6. The alternative system
The production of C3b can be catalyzed by “C3 convertase.”
C3 convertase is
produced by C3b
associating with factor
B in the presence of
Mg++ to form C3bB
which in the presence
of factor D is cleaved to
C3[bBb].
Nota bene: C3[bBb] is C3 convertase.
{Here brackets
substitute for a
horizontal bar above
the letters bBb; by
convention, the bar
over the letters means
that the complex has
enzymatic activity.}
7. The alternative system
The production of C3b can be catalyzed by “C3 convertase.”
Because C3 convertase
both creates and
contains C3b, the
complex mediates a
“positive feedback”
system.
Thus, the reaction has
the potential “to run
away” or “explode.”
Factor H can displace
factor B. The C3bH complex is
the substrate of factor I which
inactivates C3b by cleaving it into
C3d and C3g.
C3[bBb] is C3 convertase.
8. The alternative system
• C3b has FOUR fates:
(i) it can bind to a microbial surface;
(ii) it can associate with factor B;
(iii) it can associate with factor H; or
(iv) it can bind another C3b.
(What happens here?)
The half-life of C3b is approximately 100
microseconds (so the “choices” occur quickly!).
9. The alternative system
If C3[bBb] binds a
second C3b, it
becomes
C3[bBb]3b
which is “C5
convertase”.
C5 convertase cleaves C5 into
C5a and C5b.
C5b is unstable and is stabilized
by C6.
C5b6 allows C6 and C7 to
associate and penetrate a
membrane.
The C5b67 recruits C8 which
organizes C9 to form a
“membrane attack complex”
(MAC).
10. The alternative system
C5 convertase cleaves C5 into C5a and C5b.
C5b is unstable and is stabilized by C6.
C5b6 allows C6 and C7 to associate and penetrate a
membrane.
The C5b67 recruits C8 which organizes C9 to form a
“membrane attack complex” (MAC).
11. The alternative system
• Finally….
–C3a and C5a are
–CHEMOATTRACTANTS!
Think of the multiple dimensions of this system which,
incredibly, is the product of evolution. A great puzzle is how
such interdependent systems can emerge incrementally.
12. The CLASSICAL pathway
Stimulated by antibodies:
specifically: IgM and IgG
(subclasses 1, 2, 3)
Start with C1q a HUGE
protein (410,000 daltons!)
Composed of 18 peptides.
Peptides can associate to
form trimers; six sets of
trimers make C1q.
C1q has helical “stalks” and
globular “heads.”
(N. B. the heads are the
carboxy end and the stalks
are the amino ends)
13. The CLASSICAL pathway
Also associated
with C1 are C1r
and C1s which
associate to
make dimeric
pairs (C1r2s2);
the dimeric pair
joins C1q to form
C1qr2s2.
14. The CLASSICAL pathway
• C1qr2s2 binds to TWO immunoglobulins.
– The complement binding sites of circulating
IgM are too far apart to bind complement;
– only when IgM is bound does it fold so that
C1qr2s2 can “see” nearby complement binding
domains.
– IgG concentrations must be high in the vicinity
of antigens for threshold levels of complement
binding domains to be present.
15. The CLASSICAL pathway
When C1qr2s2 is bound to requisite number of
immunoglobulins, C1r “autocatalytically” converts to C1[r].
C1[r], in turn, converts C1s to C1[s].
C1[s] cleaves C2 and C4.
C4 is cleaved to C4a and C4b; C4b associates with its
“target” which is C2.
C2 is cleaved by C1[s] making C[4b2a] which is a C3
convertase! (Note that 2a is bigger than 2b, this nomenclature being the on
exception to the convention that “a” is smaller than “b.”)
As with the other C3 convertase, C3b can join C[4b2a] to
make C[4b2a]3b which is also a C5 convertase.
20. The LECTIN pathway
Lectins are proteins which bind to carbohydrates.
Many bacteria have many mannose residues on
their surface. The lectin-based complement
system begins with a “mannose-binding protein”
(MBP).
MBP reacts, in turn, with a MBP-associated
serine protease (MASP).
MASP functions, in effect, like activated C1q[r2s2],
that is a C3 convertase.
