Review
The molecular architecture of the TNF superfamily

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Abstract

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.

Section snippets

The TNF family

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

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 structures are available for the THD of TNF 20, 21, LTα [22], CD40L [23] and TRAIL 24, 25, 26, 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’

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

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

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

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

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

Interactions between a TNF ligand and a TNF receptor

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 TRAIL-R2, confirming that the 3:3 stoichiometry is the likely basis of the

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

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.

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