Fas-FADD
Death Domain Complex
Jackie Shirreffs '11 and Mac Woods '10
Contents:
I.
Introduction
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
complex
is the initiating factor for DISC
formation by
creating a receptor platform for the recruitment of
procaspase 8, which begins a series of interactions that eventually
lead to programmed cell death.
A
conformational change in the Fas domain allows for the binding of FADD
protein. While the conformational change occurs a Fas-Fas complex
bridge
forms, resulting in a regulatory Fas-FADD complex. This complex
functions as a mechanistic switch, which regulates accidental
DISC
assembly, but allows for highly processive DISC formation, which leads
to cell
apoptosis. .
II.
General Structure
The
Fas-FADD death domain
consists of two tetramers, Subunit
A
and Subunit
B. Each
tetramer is made up of four Fas and four FADD
subunits.
The
Fas
subunits make up
the core of the tetramer and the FADD
subunits
make up the outer
section of the tertramer.
Each
Fas
subunit is
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,
7,
and 8.
The
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
molecules.
III.
Fas Death Domain
Fas subunit undergoes
a
conformational change when the Fas-Ligand
(FasL) binds.
This
conformational
change shifts helix six away from the
deatht domain (helix 1, 2, 3
and 4).
Helix 6
fuses with helix 5 to
form the stem
helix. As the fusion occurs
the formation of the c-helix
occurs.The Fas interaction
interface
consists of the stem
helix and the c-helix.
Ile-313
unbends helix
6 and allows for the fusing of helix 5 and helix 6.
The
binding of the Fas
ligand causes the opening of helix 6. This binding is mediated by two
essential
residues Arg-279
and His-282 of helix
4
in the Fas complex, which hydrogen bond with Tyr
of
the Fas ligand.
H20
and Na
are
found between the Fas subunits and help stabilize the hydrophobic
interactions between the Leu-303,
Cys-304, Ala-307,
and Gln-311
with
the Thr-319, Ile-813, Leu-315, Gln-311,
and Ile-314.
The
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.
IV.
FADD Death Domain
The
FADD subunit must undergo a conformational change
of the
c-helix
(6th
helix).
This
conformational
change exposes the death
domain
interface
of the FADD
subunit.
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,
Cys-105
and Val-141.
A
different
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
and Gly-109
V.
Fas-FADD Interactions
The
opening of the Fas subunit
allows for the binding of the FADD
death
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
process.
Helices
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,
Leu-176, Glu-179,
Ala-183
and Gln-182
and in Fas are Lys-309,
Leu-306,
Asn-302, Ile-313,
Ile-295, and Tyr-291.
Helix
6 of the Fas
binds with helix 1 of the FADD complex. The residues Thr-235, Lys-231, Tyr-232,
and Asp-228
of the Fas complex interact with the residues Cys-98, Asn-102,
and Asp-106
of the FADD complex.
Once
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.
Proaspase-8
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.
VI.
References
Bajoratha, J. 1999. Analysis of
Fas–ligand interactions using a molecular model of the
receptor–ligand interface. Journal of Computer-Aided
Molecular Design, 13: 409–418
Berglund, H; Olerenshaw, D; Sankar, A;
Federwisch, M; McDonald, N,Q; and Driscoll, P.C. 2000 The
Three-dimensional Solution Structure and Dynamic Properties of the
Human FADD Death Domain. J. Mol. Biol. 302, 171±188.
Hill JM, Morisawa G, Kim T, Huang T, Wei Y,
Wei Y et al. 2004. Identification of an expanded binding surface on the
FADD death domain responsible for interaction with CD95/Fas. J Biol
Chem; 279: 1474–1481.
Jeong EJ, Bang S, Lee TH, Park YI, Sim WS,
Kim KS. 1999. The Solution Structure of FADD Death Domain: Strucutral
basis of the Death Domain interactions of Fas and FADD. J. Biol
Chem;274(23):16337– 16342.
Scott FL, Stec B, Pop C, Dobaczewska MK,
Lee JJ, Monosov E, Robinson H, Salvesen GS,
Schwarzenbacher R, Riedl SJ. 2009. The fas-FADD death domain complex
structure unravels
signalling by receptor clustering. Nature 457(7232):1019-22.
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