Two independent crystal structures of unbound Apo2L/ TRAIL show that it resembles the TNF trimer in its basic architecture [5,6]. Apo2L/TRAIL has two unusual features with respect to other TNF family members. First, it has a distinct, long loop between strands A and A' (residues 130 to 150) that traverses its surface but is poorly ordered or even disordered between residues 131 and 143 (Fig. 1). Second, a novel zinc-binding site buried in the trimer interface is formed by the single cysteine residue from each monomer [6,7]. This binding site appears to be unique to Apo2L/TRAIL among TNF family members. Its importance for the structural integrity and biological activity of the protein was revealed when the site was removed using chelating agents or mutation of the cysteine residue [6,8,9]. The resulting protein showed changes in its circular dichroism and trypto-phan fluorescence spectra, indicating a more open trimer, and had reduced thermal stability, receptor-binding affinity, and bioactivity. Therefore, the role of the zinc site is to stabilize the trimer and, in particular, the conformation of the adjacent loops that interact with receptor.
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