Structure Watch

One sign for many signals

Tumour-necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) — which is important for innate and adaptive immunity and for bone homeostasis — is the only member of the TRAF family that is involved in signalling from both the TNFR and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamilies. TRAF6 acts mainly through its TRAF-C domain, which does not interact with peptide motifs that are recognized by many other TRAFs, and the molecular basis of TRAF6 specificity has remained unclear. Now, however, in Nature, Wu and colleagues describe the crystal structures of TRAF-C alone and in complex with peptides from members of the TNFR superfamily (CD40 or TRANCE-R).

The structures revealed that there are marked differences in peptide binding to TRAF6 and to other TRAFs. Using structure-based sequence alignment of TRAF6-binding sites in human and mouse CD40 and TRANCE-R, the authors identified a TRAF6-binding motif — Pro-X-Glu-X-X-(Ar/Ac), where Ar is an aromatic residue and Ac is an acidic residue. The best-characterized TRAF6 signalling pathway for the IL-1R/TLR superfamily involves IRAK, an adaptor kinase that is found upstream of TRAF6, and Wu and co-workers also found TRAF6-binding motifs in three IRAKs. These results indicate that TRAF6 uses a single structural mechanism to regulate several signalling cascades. Also, because the authors found that peptides derived from the TRAF6-binding motif could inhibit TRAF6-mediated signalling, this work highlights new potential therapeutic modulators for diseases such as osteoporosis. REFERENCE Ye, H. et al. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418, 443–447 (2002)

A new snapshot

Increases in cytoplasmic Ca²⁺ levels cause skeletal muscle cells to contract. After excitation, normal Ca²⁺ levels are restored by actively pumping these ions from the cytoplasm into the sarcoplasmic reticulum (SR). The transporter that carries out this process is Ca²⁺-ATPase (a P-type ion-transporting ATPase), and the structure of Ca²⁺-ATPase in the Ca²⁺-bound form (E1Ca²⁺) has previously been determined. Now, however, a new snapshot of this transporter is available. Toyoshima and Nomura have determined the 3.1-Å-resolution crystal structure of this pump in its Ca²⁺-free (E2) state, and this second structure of the pump in its reaction cycle has allowed us to begin to understand how such ion pumps work.

The authors saw large conformational differences between the E1Ca²⁺ and E2 states. The cytoplasmic part of the pump has three domains that are widely separated in the E1Ca²⁺ state, and these domains form a compact structure in the E2 state. In addition, six of the ten transmembrane helices undergo large-scale rearrangements, and these changes are not limited to the helices that form the Ca²⁺-binding sites. The authors believe that such large, complicated movements are needed for counter-transport (two Ca²⁺ ions can be transported per ATP hydrolysed, and two or three H⁺ ions are counter-transported). In addition, these rearrangements ensure that Ca²⁺ is released into the SR lumen and that new Ca²⁺ ions can enter the pump from the cytoplasmic side. REFERENCE Toyoshima, C. & Nomura, H. Structural changes in the calcium pump accompanying the dissociation of calcium. Nature 418, 605–611 (2002)