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Review
TRENDS in Biochemical Sciences Vol.27 No.1 January 2002
19
The molecular architecture of the
TNF superfamily
Jean-Luc Bodmer, Pascal Schneider and Jürg Tschopp
Ligands of the TNF (tumour necrosis factor) superfamily have pivotal roles in
the organization and function of the immune system, and are implicated in the
aetiology of several acquired and genetic diseases. TNF ligands share a
common structural motif, the TNF homology domain (THD), which binds to
cysteine-rich domains (CRDs) of TNF receptors. CRDs are composed of
structural modules, whose variation in number and type confers heterogeneity
upon the family. Protein folds reminiscent of the THD and CRD are also found in
other protein families, raising the possibility that the mode of interaction
between TNF and TNF receptors might be conserved in other contexts.
Metazoan organisms consist of an intricate and
ordered society of individual cells that must
communicate to maintain and regulate their
functions. This is achieved through a complex and
highly regulated network of hormones, chemical
mediators, chemokines and other cytokines, acting
as ligands for intra- or extracellular receptors.
Ligands and receptors of the tumour necrosis factor
(TNF) superfamilies are examples of signal
transducers whose integrated actions impinge
principally on the development, homeostasis and
adaptative responses of the immune system. Despite
their varied and pleiotropic actions, members of the
TNF ligand and receptor (TNFR) families have
remarkably similar structures, and their mode of
interaction is conserved. The aim of this review is to
provide an overview of the molecular architecture
and the modular organization of the TNF and TNFR
gene superfamilies.
The TNF family
Jürg Tschopp*
Pascal Schneider
Jean-Luc Bodmer
Institute of Biochemistry,
University of Lausanne,
Chemin des
Boveresses 155,
1066 Epalinges,
Switzerland.
*e-mail: [email protected]
ib.unil.ch
The TNF ligand family comprises 18 genes encoding
19 type II (i.e. intracellular N terminus and
extracellular C terminus) transmembrane proteins,
characterized by a conserved C-terminal domain
coined the ‘TNF homology domain’ (THD) (Fig. 1).
This trimeric domain is responsible for receptor
binding and its sequence identity between family
members is ~20–30%. Although most ligands are
synthesized as membrane-bound proteins, soluble
forms can be generated by limited proteolysis (Fig. 1).
Distinct proteases are involved in this process,
depending on the ligand: metalloproteases of the
ADAM (a disintegrin and metalloproteinase domain)
family act on TNF and RANKL ligands [1,2],
matrilysin acts on Fas ligand (FasL) [3], and
members of the subtilisin-like furin family act on
BAFF, EDA, TWEAK and APRIL-members of the
TNF family [4,5]. Solubilization is essential for the
physiological function of some ligands: mutation in
http://tibs.trends.com
the furin recognition sequence of EDA is a frequent
cause of the genetic disorder X-linked hypohidrotic
ectodermal dysplasia (XLHED) [4,6]. By contrast, the
shedding of some ligands inhibits their function. For
instance, the cytotoxic activity of FasL is
dramatically downregulated upon cleavage [7].
The N terminus of lymphotoxin α (LTα) resembles a
signal peptide, making its conversion to a soluble
form extremely efficient. Consequently, LTα is
never found at the cell surface except when it is
associated with membrane-bound LTβ as
LTα1β2 heterocomplexes [8] (Fig. 1). Processing of
TNF-related apoptosis-inducing ligand (TRAIL) by a
cysteine protease has been proposed [9], but the
resulting soluble form seems to be too small to retain
a functional THD.
Ligands of the TNF family control and orchestrate
the immune and inflammatory responses at several
levels (recently reviewed in Ref. [10]). During
development, TNF ligands such as TNF, LTα, LTβ
and RANKL provide crucial signals for the
morphogenesis of secondary lymphoid organs [10,11].
In addition, the grooming and proper activation of
immune precursor cells to fully competent effectors is
dependent on several other TNF family members
such as BAFF and CD40L for B lymphocytes [12–14];
4-1BBL, OX40L and CD27L for T lymphocytes [15];
and CD40L and RANKL for dendritic cells [16,17].
Pro-apoptotic members of the family (e.g. TNF, FasL
and TRAIL) contribute to the function of cytotoxic
effector cells and participate in the homeostasis of the
lymphoid compartment by evoking activationinduced cell death in immune effector cells that have
fulfilled their function [18]. Recent evidence indicates
that other TNF family ligands regulate the
development and differentiation of epithelial
structures (the EDA ligand), endothelial cells
(VEGI and TWEAK) and bone-resorbing osteoclasts
(RANKL and TNF) [10].
TNF family ligands and receptors are associated
with several disease conditions that result from
acquired processes or genetic defects. Acquired acute
or chronic inflammatory conditions such as septic
shock or rheumatoid arthritis result from excessive or
inappropriate TNF expression [19]. Mutations in TNF
ligands and/or receptors have been described in five
hereditary diseases: hyper IgM syndrome (HIM,
CD40L), type I autoimmune lymphoproliferative
syndrome (ALPS, Fas/FasL), TNF-R1-associated
periodic fever syndrome (TRAPS, TNF-R1),
0968-0004/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0004(01)01995-8
Review
20
58
TRENDS in Biochemical Sciences Vol.27 No.1 January 2002
21
80
37
25
11
16
37
22
18
VEGI
23
LIGHT
LTα1β2
CD30L
FasL
28
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TWEAK
RANKL
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CD27L
LTα
TNFα
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BAFF
Modules:
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236
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Ti BS
Fig. 1. Interactions between ligands and receptors of the human tumour necrosis factor (TNF) family:
TNF ligands (top) and TNF receptors (bottom). The TNF ligands are represented as type II homo- or
heterotrimeric transmembrane proteins (with the exception of VEGI, which lacks a predicted
transmembrane domain and is therefore drawn as a soluble ligand). TNF homology domains (THDs)
are shown as green boxes. Filled black arrowheads indicate processing by furin family members, and
open black arrowheads by other types of proteases. The TNF receptors are typically type I or type III
transmembrane proteins, but also occur as glycolipid-anchored or soluble proteins. N1, A1, A2, B1,
B2, C2 and X2 modules are colour-coded as shown in the inset. The positions of individual cysteines
are indicated by horizontal bars, and stars show modules whose cysteine pattern does not conform
entirely to that of cannonical A, B, C and N modules. The lengths of intracellular domains are indicated
for each ligand and each receptor, and the intracellular homology domains, known as the ‘death
domains’, are indicated as red boxes. Red arrows show documented interactions. An interaction
between TWEAK and TRAMP has been reported [53] but has not yet been confirmed. Some of the
ligands and receptors have several commonly used names: FasL/CD95L, TRAIL/Apo-2L,
RANKL/OPGL/TRANCE, BAFF/BLyS/TALL-1, Fas/CD95, TRAIL-R1/DR4, TRAIL-R2/DR5, TRAIL-R3/DcR1,
TRAIL-R4/DcR2, TRAMP/DR3 and TROY/TAJ. For the official TNF superfamily (TNFSF) nomenclature
and additional synonyms, consult http://www.gene.ucl.ac.uk/nomenclature/genefamily/tnftop.html
hypohidrotic ectodermal dysplasia (HED,
EDA/EDAR) and familial expansile osteolysis (FEO,
RANK) [10]. It is likely that other links between TNF
members and diseases will be uncovered in the future.
Structural features of TNF family ligands
The THD is a 150 amino acid long sequence
containing a conserved framework of aromatic and
hydrophobic residues (Fig. 2). To date, atomic-level
http://tibs.trends.com
structures are available for the THD of TNF [20,21],
LTα [22], CD40L [23] and TRAIL [24–27]. THDs
share a virtually identical tertiary fold and associate
to form trimeric proteins (Fig. 3a). The THDs
are β-sandwich structures containing two stacked
β-pleated sheets each formed by five anti-parallel
β strands that adopt a classical ‘jelly-roll’ topology.
The inner sheet (strands A, A′, H, C and F) is
involved in trimer contacts, and the outer sheet
(strands B, B′, D, E and G) is exposed at the surface.
Trimeric THDs are ~60 Å in height and resemble
bell-shaped, truncated pyramids with variable loops
protruding out of a compact core of conserved
anti-parallel β strands (Figs 2,3a). TRAIL is unique
with respect to the AA′ loop, which contains a
15 residue-long insertion that spans the whole outer
surface of the monomer [24,26,27]. The trimer is
assembled such that one edge of each subunit
(strands E and F) is packed against the inner sheet
of its neighbour, forming large and mostly
hydrophobic interfaces, resulting in a very stable
interaction [20,26,27]. TNF and CD40L contain a
single disulfide bridge linking the CD and EF loops
[20,23] (Fig. 3a). Similar disulfide links are
Review
TNF
hTNFα
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TRENDS in Biochemical Sciences Vol.27 No.1 January 2002
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G
G
G
S
G
G
G
G
G
K
Q
R
A
E
S
E
S
P
E
Q
A
A
P
V
R
V
V
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
H
I
F
S
S
S
C
S
S
S
S
A
A
G
S
S
S
C
G
I
C
F
L
Q
Q
L
K
Q
K
Q
N
Q
Q
Q
Q
Q
Q
Q
Q
Q
Q
K
L
V
G
Q
T
Y
Y
C
T
L
L
E
H
A
T
Q
E
Y
V
V
V
V
V
V
T
I
V
V
V
V
V
V
V
V
L
L
G
V
V
L
I
L
V
L
L
I
V
V
I
L
L
L
L
L
L
I
L
L
L
L
I
Q
K
R
H
H
K
Q
E
P
L
Q
D
L
L
L
L
L
L
M
L
L
L
L
L
Q
E
Q
D
E
A
E
N
Q
R
R
T
Q
Q
V
A
V
K
K
Y
A
P
P
E
R
K
K
K
K
R
T
K
V
I
I
I
F
F
F
F
F
F
F
F
F
F
F
F
V
T
T
T
H
G
I
R
T
T
T
T
C
C
C
C
C
A
A
I
A
C
C
C
G
G
G
G
G
A
N
G
G
G
G
R
R
G
G
G
N
H
K
D
D
E
E
D
D
D
E
A
D
D
Q
Q
S
D
D
V
L
D
R
Q
R
E
K
H
R
E
S
E
I
K
K
S
T
T
D
H
K
L
L
V
V
L
L
I
I
V
L
L
I
I
L
I
L
T
T
V
G
G
G
G
G
G
G
G
G
G
N
N
D
E
E
D
D
D
D
Q
D
D
D
D
Q
N
E
E
Q
E
R
E
T
R
Q
Q
G
A
G
T
S
E
E
T
T
N
N
K
Y
S
C
V
V
L
K
-
7
11
13
8
17
5
9
11
9
2
2
5
5
5
5
11
6
9
1
T
K
K
N
N
P
P
P
P
E
P
Q
V
V
V
I
I
V
R
Y
L
V
V
I
P
P
P
P
P
S
K
L
A
P
G
P
G
G
G
G
G
G
G
G
G
G
G
G
S
S
Y
V
M
Y
F
S
F
Q
S
A
A
R
D
C
F
E
Y
A
T
V
V
V
V
V
I
V
L
V
V
V
I
L
T
Q
A
L
E
H
N
R
N
N
S
E
N
A
I
K
K
R
I
N
Y
R
N
I
T
I
V
V
V
V
V
V
I
I
M
M
T
F
L
I
A
V
Y
L
L
T
L
V
I
V
R
V
V
I
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
D
S
L
S
S
T
S
T
P
P
V
V
L
N
T
D
R
T
R
G
H
D
D
E
N
N
D
R
R
H
H
P
S
G
T
H
T
Y
Y
Y
F
Y
F
S
V
L
Y
Y
Y
F
F
F
F
F
F
F
F
L
F
F
F
T
T
V
T
A
T
N
K
S
A
A
S
V
V
V
V
V
V
A
V
V
V
V
V
W
F
W
F
W
W
Y
W
C
F
W
W
V
L
L
I
L
L
L
L
V
L
V
L
Y
Q
-
L
L
L
I
I
L
M
L
F
M
M
S
S
L
F
L
L
L
I
T
A
R
T
T
S
V
M
I
G
G
Y
Y
D
E
A
K
A
S
H
H
S
H
V
H
Q
V
A
H
Q
E
E
L
V
V
L
L
L
T
E
S
G
V
K
Y
Y
S
L
V
V
V
L
R
G
E
H
H
I
V
L
L
I
V
I
V
L
I
V
V
V
V
L
I
L
L
Y
S
Q
Y
Y
T
Y
Y
T
C
Q
S
V
V
D
Y
C
L
Q
Q
R
L
R
K
K
M
K
K
L
R
R
D
D
G
K
S
I
P
K
I
F
A
R
V
R
Y
T
K
K
E
E
E
N
P
N
L
D
hTNFα
hLTα
hLTβ
hLIGHT
hVEGI
hFasL
hTRAIL
hTRANCE
hCD40L
hBAFF
hAPRIL
hEDA-A1
hEDA-A2
hTWEAK
hGITRL
hCD27L
hCD30L
h4-1BBL
hOX40L
N
hC1qA
hC1qB
hC1qC
hCRF
hACRP30
hCORS26
hPrecerebellin
hMultimerin
hEMILIN-1
hCollVIIIa1
hCollVIIIa2
hCollXa1
N
hTNFα
hLTα
hLTβ
hLIGHT
hVEGI
hFasL
hTRAIL
hTRANCE
hCD40L
hBAFF
hAPRIL
hEDA-A1
hEDA-A2
hTWEAK
hGITRL
hCD27L
hCD30L
h4-1BBL
hOX40L
C
D
F
Y
Y
Y
Y
F
F
Y
A
Y
Y
Y
Q
H
H
H
H
S
H
T
V
H
H
H
11
10
10
11
11
10
10
10
10
11
11
11
11
10
8
10
9
8
19
V
A
A
V
I
M
V
I
L
V
V
V
V
V
T
S
T
T
S
T
T
T
T
T
T
T
T
T
S
T
Q
L
S
S
L
T
M
V
E
T
H
H
H
Y
F
F
Y
F
F
F
Y
S
F
F
F
F
Y
Y
F
I
V
N
S
S
H
M
V
K
K
S
G
C
V
V
F
F
F
F
F
F
F
F
F
F
L
F
F
F
W
F
F
L
P
G
M
M
V
V
V
A
V
A
L
A
A
A
Q
R
V
M
Q
Q
H
K
V
I
I
G
N
C
Q
V
E
G
G
G
G
G
G
F
H
S
D
D
Y
Y
E
A
I
V
R
Q
K
S
R
G
R
R
R
R
C
T
Q
Y
Y
D
N
A
L
R
S
F
F
Y
L
F
F
F
F
F
Y
F
V
F
P
L
F
L
F
C
F
F
F
F
I
Y
Y
F
E
Y
Y
Y
Y
P
P
P
T
P
N
H
N
K
K
Q
L
L
T
L
H
Q
A
N
21
I
L
L
L
V
L
L
I
K
V
V
L
3
3
3
11
4
10
10
4
4
8
8
8
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
G
L
G
G
I
A
A
A
A
L
A
A
L
A
F
A
A
L
I
V
Y
L
E
I
F
V
F
F
Y
F
F
L
L
V
I
I
F
I
Q
S
F
F
A
A
M
M
L
K
L
K
K
K
K
R
R
Q
L
W
N
R
C
L
L
V
V
L
L
V
V
L
L
L
L
L
V
L
V
S
V
V
L
L
L
I
L
L
L
L
L
L
L
L
I
L
L
I
L
L
V
L
L
L
L
V
F
F
F
Y
Y
F
F
Y
Y
Y
C
A
C
C
C
C
K
M
M
S
V
W
W
Y
L
V
V
K
V
H
L
G
E
V
V
K
S
N
L
N
S
N
N
F
A
A
A
N
I
L
L
G
L
G
G
L
V
L
L
G
0
0
1
0
0
0
1
4
0
1
0
6
6
1
7
2
1
14
1
V
M
Y
Q
F
N
W
V
L
F
Y
T
S
R
R
V
K
T
P
V
S
K
K
P
S
G
S
R
K
V
V
D
R
N
N
V
H
E
Q
A
K
Q
R
K
R
D
Q
Q
Q
K
A
V
L
V
M
L
L
L
M
I
L
D
T
N
D
Y
G
E
A
V
P
P
P
13
12
12
12
15
11
10
11
11
14
14
14
S
S
S
S
S
S
S
T
T
S
S
S
V
I
V
T
T
T
T
T
I
S
S
S
F
F
F
F
F
F
F
F
F
F
F
F
S
S
S
S
T
A
S
S
S
S
S
S
G
G
G
G
G
G
G
G
G
G
G
G
F
F
F
F
F
F
F
Y
A
Y
F
F
P
P
P
S
H
E
P
R
G
P
P
P
S
D
D
D
D
T
L
T
D
M
T
M
1
3
0
0
2
1
0
0
6
0
0
0
hC1qA
hC1qB
hC1qC
hCRF
hACRP30
hCORS26
hPrecerebellin
hMultimerin
hEMILIN-1
hCollVIIIa1
hCollVIIIa2
hCollXa1
C
Ti BS
Fig. 2. Sequence alignment of the human tumour necrosis factor (TNF) and C1q
superfamilies. Primary sequence alignments of the TNF homology domains (THDs)
of 19 TNF ligands (including the distantly related member OX40L) and of 12 published
C1q-related proteins. The alignment has been reduced to regions of significant
sequence homology. Intervening loops have been omitted except for the conserved
L/VxW motif in the AA’ loop of the TNF ligands, but their length is indicated. The
individual β strands (A–H) are highlighted with boxes coloured with respect to their
succession in the primary structure from red to magenta. Blue dots above the
alignment indicate residues involved in monomer–monomer interface formation and
http://tibs.trends.com
their numbers represent the frequency at which each position is found to interact in
the five structures available (e.g. TNF, LTα, CD40L, TRAIL and mACRP30). Red squares
represent residues involved in receptor binding in the two complex structures
available (LTα–TNF-R1 and TRAIL–DR5). Arrowheads underneath the sequences
point to the four conserved residues in the TNF and C1q families. The multiple
sequence alignment was generated with the amino acid sequence of THD and gC1q
domains using ClustalW, and was edited manually to account for structural
knowledge. Identical amino acids (white text on black background) and 50% similar
amino acids (on grey background) were shaded using Boxshade.
22
Review
TRENDS in Biochemical Sciences Vol.27 No.1 January 2002
(a) TNF
(b) ACRP30
(c) Poliovirus
CD
loop
EF
loop
F
AA′
loop
A′
A
E
C
B′
A′
E
H C
B′
H
A
D
D
F
B
A
G
FB
G
H
B G
E
D
C
DE loop
Membrane
Collagen domain
H
F
F
E
C
H
C
D
A′
A
A′
G
B
B′
A B′ B
E
D
G
DE loop
AA′ loop
10 Å
Fig. 3. The tumour necrosis factor (TNF) homology domain (THD).
(a) Ribbon diagrams of the THD of human TNF seen from the side (top)
and top (bottom) orientation. One monomer is highlighted and the
other two are shaded. The ten anti-parallel β strands (designated A, A′,
B′, B, C, D, E, F, G and H according to Ref. [20]) are coloured using the
same code as in Fig. 2. Intervening loops are shown in white. The
orientation of the THD relative to the membrane is indicated. Note the
close proximity of N and C termini. Models are based on the PDB atomic
coordinate file 1TNF [20]. (b) Structure of the gC1q domain of murine
ACRP30 seen from the side (top) and top (bottom) orientation showing
its similarity to the THD. Models are based on the PDB atomic
coordinate file 1C28 [31]. (c) Representation of the pentameric ‘jelly-roll’
domain of the VP1 capsid protein (boxed in the representation of the
viral particle in the centre) of the Mahoney strain of type 1 human
poliovirus seen from the side (top) and top (bottom) orientation.
Strands are coloured and numbered as in (a) and (b). The topological
organization of the eight strands is identical to that of the THD, with the
exception of the two interruptions in strands A and B. Models are based
on the PDB atomic coordinate file 2PLV [36].
predicted to occur in FasL, LIGHT, VEGI, CD30L
and CD27L, whereas TWEAK, EDA, APRIL and
BAFF have a predicted disulfide bridge between
β strands E and F. In TRAIL, a single cysteine
residue (Cys230) in the EF loop is involved in the
coordination of a Zn(II) ion, with each monomer
contributing to one coordination position; the fourth
coordination position is occupied by an internal
solvent molecule or a chloride counter-ion [24–26].
This metal-binding site is unique so far in the TNF
family, and affects the stability and bioactivity of
TRAIL [26,28,29]. Incomplete Zn coordination, and
formation of partially oxidized, disulfide-linked
species of TRAIL, have recently been suggested to
account for its hepatotoxicity [30].
http://tibs.trends.com
10 Å
10 Å
TNF-related structures – the C1q family
Crystallographic studies revealed that TNF and the
globular gC1q domain of mouse ACRP30 have a
closely related tertiary structure and trimeric
organization, suggestive of an evolutionary link
between the TNF and C1q families [31] (Fig. 3a,b).
The human C1q gene family comprises, so far,
13 members (Fig. 2), which are characterized by the
presence of a trimeric globular C-terminal domain,
known as gC1q. The prototypical member of the
family is C1q, a bouquet-like molecule comprising
18 chains (six each of C1qA, C1qB and C1qC) that
associate into six heterotrimeric gC1q domains held
together by a bundle of collagen domains. C1q
recognizes immune complexes and triggers the
classical complement pathway (recently reviewed in
Ref. [32]). The C1q family also contains several
collagenous members (CRF, ACRP30, CORS26,
EMILIN-1 and -2, and collagens VII and X) and two
non-collagenous members (Precerebellin and
Multimerin) (Fig. 2). Many of these proteins are
components of the extracellular matrix in diverse
organs [32]. ACRP30 is an abundant serum protein
that is synthesized by adipose tissues in response to
insulin, and is downregulated in obese mouse and
humans [33,34]. The homologues of ACRP30 are
drastically downregulated in the serum of
hibernating Siberian chipmunks, pointing to a role in
energy metabolism. Indeed, ACRP30 induces weight
loss in mice via activation of fatty acid catabolism [35].
Conserved residues of gC1q domains are located
Review
TRENDS in Biochemical Sciences Vol.27 No.1 January 2002
within the core β strands, as previously discussed for
THD domains. Although the sequence identity
between the two families is reduced to only four
amino acid residues (indicated with arrowheads in
Fig. 2), the overall hydrophobic character of the
internal β-pleated sheet is maintained in both
families.
To date, there is no evidence that the mode of
interaction described in the TNF family also applies
to proteins containing globular C1q domains. Several
C1q receptors have been described, but none of them,
with the notable exception of the immune complex,
binds to the globular domain. Nevertheless, the
recent demonstration that the gC1q domain of
ACRP30 is biologically active implies the existence of
ACRP30 receptor(s), which could be structurally
related to TNF receptors.
TNF-related structures – viral capsid proteins
As first noticed by Jones and Eck in 1989, the overall
fold and topology of the THD is very similar to that
of the capsid proteins of small spherical plant
viruses (e.g. Tomato Bushy Stunt Virus and Satellite
Tobacco Necrosis Virus) and mammalian
picornaviruses (including the common human
Rhinoviruses, the Foot-and-Mouth Disease Virus
and Poliovirus), despite there being no detectable
similarity at the primary sequence level [20,21].
Although these capsid proteins associate along a
fivefold instead of a threefold axis of symmetry, the
connectivity of their β strands is identical to that of
the THD, with the exception that strands A and
B are not interrupted by loops [36] (Fig. 3c). These
fivefold structures appear on the virus surface as
12 broad, star-like protuberances (Fig. 3c). Although
the structural relationship existing between
these apparently unrelated protein families
highlights the propensity of ‘jelly-roll’ motifs to
oligomerize, there appears to be no functional
conservation between TNF family members and
icosahedral viral capsid proteins. Indeed, the
receptors allowing entry of this class of viruses into
cells do not belong to the TNF receptor family and do
not bind directly to the oligomeric ‘jelly-roll’
structure [37].
The TNF receptor family
In humans, 29 TNF receptors have so far been
identified (Fig. 1). These are primarily type I
(extracellular N terminus, intracellular C terminus)
transmembrane proteins, but there are exceptions
to this rule: BCMA, TACI, BAFFR and XEDAR are
type III transmembrane proteins (lacking a signal
peptide), TRAIL-R3 is anchored by a covalently
linked C-terminal glycolipid, and OPG and DcR3 lack
a membrane-interacting domain and are therefore
secreted as soluble proteins. Soluble receptors can
also be generated by proteolytic processing (CD27,
CD30, CD40, TNF-R1 and TNF-R2) [38], or by
alternative splicing of the exon encoding the
http://tibs.trends.com
23
transmembrane domain (Fas and 4-1BB) [39]. The
essential role of these soluble receptors in modulating
the activity of their cognate ligands has been welldocumented (for OPG and TNF-R1 examples, see
Refs [40,41]). In addition, several viral open reading
frames encode receptor homologues that interact
with TNF and that are believed to interfere with the
onset of inflammatory responses: SVF-T2 in Shopefibroma virus,Va53R in Vaccinia, and cytokine
response modifiers CrmB, CrmC and CrmD in
orthopoxviruses (reviewed in Ref. [39]). The TNF
receptor family member NGFR is unique in that it
binds low-affinity ligands that do not belong to the
TNF family. These ligands (NGF, BDNF and
neurotrophins) also engage a family of high-affinity
tyrosine receptor kinases (trkA, B and C), which are
unrelated to TNF receptors [42]. The existence of a
bona fide TNF ligand for NGFR cannot be excluded at
present.
Structural features of the TNF receptor family
The extracellular domains of TNF receptors are
characterized by the presence of cysteine-rich
domains (CRDs), which are pseudo-repeats typically
containing six cysteine residues engaged in the
formation of three disulfide bonds. The number of
CRDs in a given receptor varies from one to four,
except in the case of CD30 where the three CRDs
have been partially duplicated in the human but not
in the mouse sequence. The repeated and regular
arrangement of CRDs confers an elongated shape
upon the receptors, which is stabilized by a slightly
twisted ladder of disulfide bridges (Figs 1,4).
Sequence alignment of TNF receptor family
members in the absence of structural information is
difficult because the spacing of cysteine residues is
not always conserved between receptors. Naismith
and Sprang have introduced a classification based
on distinct structural modules that greatly
facilitates sequence comparison between TNF
receptors [43]. Each module type is designated by a
letter (A, B, C and N for crystallized modules, and X
for modules of unknown structure), and by a
numeral indicating the number of disulfide bridges
it contains. A typical CRD is usually composed of an
A1–B2 or A2–B1 module or, less frequently, a
different pair of modules. A1 modules are 12–27
amino acids long, consist of three short β strands
linked by turns, and contain a single disulfide
bridge connecting strands 1 and 3, yielding a
characteristic C-shaped structure (Fig. 4). A2
modules contain a second disulfide bridge linking
the second and third strands without affecting the
overall structure. B modules are 21–24 amino acids
long and comprise three anti-parallel strands
adopting an S-shaped fold reminiscent of a paper
clip (Fig. 4). In this case, the fold is constrained by
two entangled disulfide bridges linking strands 1
and 3 in B2 modules. The first disulfide bridge is
replaced by a hydrogen bond in B1 modules [43].
24
Review
TRENDS in Biochemical Sciences Vol.27 No.1 January 2002
A1 module
hTNF-R1 ED
(3 CRD)
hLaminin
(3 × EGF)
N
Additional SS-bridge
in A2 modules
B2
N
A1
Aromatic residue (φ)
S1
C
C1-x2-G-x-φ-x-x4–9-C2
B2
N
A1
A1
B2
B2
+
S1
A1
B2 module
A1
C
N
B2
B2
A1B2 domain
Cys-rich domain
C
C1-x2–3-C2-x2–4-G-x6-C3-T-x3-N/D-T-V-C4
A1
S1
C
A1
Ti BS
Fig. 4. Modular organization of the extracellular domain of the tumour
necrosis factor (TNF) receptors. Ribbon representation of an A1 module
(light blue, top left) and a B2 module (dark blue, bottom left) along with
their consensus sequence. In the middle, the two modules are
combined to generate a cysteine rich domain (CRD). The full
extracellular domain contains several CRDs stacked on top of each
other. The tertiary structure of the epidermal growth factor (EGF)
domains of human laminin γ1 chain is remarkably similar, except that
an additional loop is inserted between CRDs (S1, shown in white).
Models are based on the PDB atomic coordinate files 1TNR
(TNF receptor) [22] and 1KLO (laminin γ1) [48].
The structure of A and B modules is also reflected at
the level of the primary sequence by the
conservation of a few non-cysteine residues. Other
modules are less frequent. So far, the N-terminal N1
modules have been found only in the TRAIL
receptors, in which they precede the first A1–B2
CRD. Structurally, the N1 module resembles the
second half of a B module [24,25,27]. The fourth
CRD of TNF-R1 contains an A1–C2 module pair, in
which the cysteine connectivity of C2 is distinct
from that of a B2 module. TACI, BCMA and Fn14
also contain putative A1–C2 CRDs, but these
remain to be demonstrated at the structural level.
Finally, we have collectively designated, as X2, four
unrelated modules of unknown structure that are
found in TRAMP, GITR, BAFFR and viral CrmC.
The recently described BAFF receptor (BAFFR) [44]
contains a single X2 module whose sequence
resembles an A module entangled with the
beginning of a B module. More structural work is
needed to understand the molecular interaction of
this receptor with BAFF. TNF receptors are often
viewed as monomers, principally because they
http://tibs.trends.com
appear in this form in crystal structures of
ligand–receptor complexes. However, TNF-R1 has
also been crystallized as both head-to-head and
head-to-tail dimers [45], and there is genetic and
experimental evidence that Fas, TNF-R1 and
CD40 exist as preformed oligomers within the
plasma membrane [46]. Self-association of the
receptors depends on an N-terminal pre-ligand
association domain (PLAD) that includes the first
CRD and that is not directly involved in ligand
binding.
TNFR-related structures – the EGF-like domain
A1 and B2 modules are not restricted to the TNF
receptor family but also form the structural basis of
epidermal growth factor (EGF)-like domains present
in several proteins such as laminins. Laminins are
composed of three related chains (α, β and γ, of which
there are different isoforms) associated by a
C-terminal coiled-coil domain. These chains display
several globular domains in their N-terminal moieties
with intervening, elongated structures composed of
EGF-like repeats [47]. As shown in Fig. 4, the overall
structure of EGF-like and CRD repeats is strikingly
similar, except that A1–B2 modules in laminin are
separated by an additional module, which we have
designated S1 because of its small size [48]. EGF-like
repeats 3–5 of the γ1 chain of laminin bind Nidogen-1,
a protein that interconnects laminin molecules in the
basement membrane, but whose sequence is
unrelated to TNF or C1q family members. So far,
there is no evidence that EGF-like repeats bind
TNF- or C1q-like ligands.
Review
(a)
TRENDS in Biochemical Sciences Vol.27 No.1 January 2002
(b)
N
CRD1
A1
DE
CRD2
AA′
B2
A1
CRD3
GH
CD
EF
C
Fig. 5. Receptor–ligand interactions. Ribbon and space-filling representations of the lymphotoxin α
(LTα)–TNF-R1 (tumor necrosis factor receptor) 3:3 complex. LTα is shown in green, TNF-R1 in blue, and
the two interaction surfaces in red and orange, respectively. In panel (a), the side chain of Tyr142 is
shown. (b) An open-book representation revealing the interaction regions. Loops, modules and
cysteine-rich domains (CRDs) contributing to these interaction surfaces are identified. Models are
based on the PDB atomic coordinate files 1TNR [22].
Interactions between a TNF ligand and a TNF receptor
Acknowledgements
We thank Kimberly Burns
for critical reading of the
manuscript. The
molecular models shown
in this publication were
generated using
Swiss-PDB Viewer v3.7 β 2
[52], which can be freely
downloaded from
http://www.expasy.ch/
spdbv/. This work was
supported by grants from
the Swiss National
Science Foundation to P.S.
and J.T.
In 1993, Banner and colleagues [22] published a
seminal study unravelling the first structure of a
TNF ligand (LTα) bound to its cognate receptor
(TNF-R1). The asymmetric unit contains three
receptors and three ligands assembled as a
hexameric complex in which a single TNF trimer
binds to three receptor molecules (Fig. 5). More
recently, highly similar crystal structures have been
reported for complexes between TRAIL and TRAILR2, confirming that the 3:3 stoichiometry is the
likely basis of the signalling unit [24,25,27]. Indeed,
the geometry of the receptor–ligand complex
matches that of TRAF-2, a trimeric intracellular
adaptor molecule mediating TNF-R2 and CD40
signals [49]. The recently identified receptors
BCMA, TACI, BAFFR and Fn14 do not contain the
A1–B2–A1 succession of modules involved in the
binding of both TNFR1 and TRAIL-R2 to their
respective ligands, implying that distinct
receptor–ligand interfaces must exist. However, the
threefold geometry is also likely to be conserved for
these ligand–receptor complexes.
The receptor molecules bind with their long axis
roughly parallel to the C3 symmetry-axis of the
trimeric ligand, in the groove formed by the
interface of each pair of monomers. Conformational
changes occurring upon complex formation are
relatively minor, and only substantially affect
receptor-contacting loops of the ligand (CD and AA′)
[22,25]. There are mainly two contact regions
between the receptor and the ligand. The first
contact area involves receptor residues
corresponding to the second CRD of the receptor
(A1 plus half of B2), and loops DE and AA′ of two
adjacent ligand subunits (Fig. 5, region shown in
red). This area is based on a central hydrophobic
interaction containing a relatively conserved
tyrosine residue (present in loop DE of TNF, LTα,
http://tibs.trends.com
25
FasL, TRAIL, LIGHT and VEGI) that is crucial for
receptor binding in TNF, LTα, FasL and TRAIL. In
the second, more polar, interaction region, the
remainder of the second CRD (second half of B2),
and the A1 module of the third CRD, of TNF-R1
make contacts with the CD and EF loops of two
adjacent ligand subunits (Fig. 5, region shown in
orange). In addition, Cha and colleagues have
provided evidence for the existence of a third,
central interaction region in their TRAIL–TRAILR2 structure. The central region involves residues
131–135 of the AA′ loop that penetrates into the
central interaction region upon binding, forming
several specific polar interactions. This additional
interaction patch might well be specific to TRAIL
because of its long AA′ loop [24].
As expected, regions of contact between ligands
and receptors are very diverse among family
members and contribute to the specific interaction of
ligand–receptor pairs (Fig. 2). However, prediction of
receptor–ligand interactions is not straightforward as
different ligands can bind the same receptor (e.g. both
TNF and LTα bind TNF-R1) and almost identical
ligands can bind different receptors. In this context,
the particular case of ectodysplasin A (EDA) is
interesting as two of its isoforms (namely EDA-A1
and -A2), which differ by only two amino acids,
display a mutually exclusive receptor specificity (for
EDAR and XEDAR, respectively). In this case,
removal of the residues Glu308–Val309 is predicted to
suppress a negative charge in the second receptor
interaction site of EDA [50].
The receptor Herpes virus entry mediator (HVEM)
interacts with two ligands of the TNF family (LIGHT
and LTα), but is also hijacked by the viral
glycoprotein D (gD) of herpes simplex virus. The
latter interaction involves the first B2 module of
HVEM, and is structurally unrelated to that of a
regular TNF ligand with a TNF receptor [51].
Conclusions
The past few years have witnessed a dramatic
increase in the number of the TNF and TNF receptor
family members. This was a direct consequence of
expressed sequence tag sequencing projects combined
with the development of bioinformatic tools. With the
completion of the genome sequencing project, it is now
reasonable to assume that these two families
approach their definitive sizes. They are
characterized by a conserved molecular architecture
and mode of interaction. A few more unexpected
additions might arise from expression cloning of
receptors, because their modular structure is more
diverse than that of the ligands. Conversely, novel
ligand specificities might arise from alternative splice
variants or from the heteromeric association of known
ligands. The molecular characterizations of TNF and
TNFR have provided a basis for the understanding of
their biological roles, and their implication in genetic
diseases.
26
Review
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