Death Domain Complex
Jackie Shirreffs '11 and Mac Woods '10
Apoptosis, or programmed
cell death, is induced upon the formation
of death inducing signaling
complex (DISC). Two of the main main subunits of this
complex are Fas
receptor and FADD (Fas associated death domain protein
complex), which make up a complex weighing 217,476 kDa. The Fas-FADD
is the initiating factor for DISC
creating a receptor platform for the recruitment of
procaspase 8, which begins a series of interactions that eventually
lead to programmed cell death.
conformational change in the Fas domain allows for the binding of FADD
protein. While the conformational change occurs a Fas-Fas complex
forms, resulting in a regulatory Fas-FADD complex. This complex
functions as a mechanistic switch, which regulates accidental
assembly, but allows for highly processive DISC formation, which leads
Fas-FADD death domain
consists of two tetramers, Subunit
tetramer is made up of four Fas and four FADD
subunits make up
the core of the tetramer and the FADD
make up the outer
section of the tertramer.
associated with a FADD
death domain subunit creating a Fas-FADD
copmplex bridge. The death domain complex contains eight Fas-FADD
complex bidges; 1, 2, 3, 4, 5, 6,
Fas-FADD complex bridges form a dimer with the
neighboring Fas-FADD complex bridge through associations between the
two Fas subunits.
The structure contains 12 SO4 molecules and 8 Na
Fas Death Domain
Fas subunit undergoes
conformational change when the Fas-Ligand
change shifts helix six away from the
deatht domain (helix 1, 2, 3
fuses with helix 5 to
form the stem
helix. As the fusion occurs
the formation of the c-helix
occurs.The Fas interaction
consists of the stem
helix and the c-helix.
6 and allows for the fusing of helix 5 and helix 6.
binding of the Fas
ligand causes the opening of helix 6. This binding is mediated by two
and His-282 of helix
in the Fas complex, which hydrogen bond with Tyr
the Fas ligand.
found between the Fas subunits and help stabilize the hydrophobic
interactions between the Leu-303,
the Thr-319, Ile-813, Leu-315, Gln-311,
opening of the Fas
subunit is crucial for the formation of the Fas-Fas bridge and for
the formtion of the Fas-FADD death domain complex.
FADD Death Domain
FADD subunit must undergo a conformational change
change exposes the death
of the FADD
A hydrophobic pocket
between helices 3 and 5 allows for the binding of death effector domain
(DED) through hydophic
interactions, mainly with a Phe-101,
interface in helix 4 allows for binding with procaspase-8, creating
favorable conditions for DISC complex formation. the exact binding is
not well understood but may involve residues Ala-116
opening of the Fas subunit
allows for the binding of the FADD
domain by exposing helix 2
and helix 3. FADD undergoes a conformational
change of the C-helix in order to bind to Fas.
The c-helix must shift in order to avoid a steric clash with the
C-helix of the Fas subunit, helix 2 and helix 3 are exposed in the
2 and 3 of
both Fas and FADD are similar. Helix 1 of Fas binds to helix 6 of
the FADD complex in an anitparellel orientation through electrostatic
and hydrophobic interactions. The residues involved in FADD are Asp-175, Arg-189,
and in Fas are Lys-309,
Ile-295, and Tyr-291.
6 of the Fas
binds with helix 1 of the FADD complex. The residues Thr-235, Lys-231, Tyr-232,
of the Fas complex interact with the residues Cys-98, Asn-102,
of the FADD complex.
the Fas ligand
opens the Fas subunit and FADD has bound to the death domain of the Fas
subunit the final subunit of the death domain complex binds.
binds to the death domain of FADD and completes the death domain
complex. Now DISC complex formation occurs, which leads to programed
cell death will occur.
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