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TRAIL is a tumor necrosis factor-related ligand that induces apoptosis upon binding to its death domaincontaining receptors, DR4 and DR5. Two additional TRAIL receptors, TRID/DcR1 and DcR2, lack functional death domains and function as decoy receptors for TRAIL. We have identified a fifth TRAIL receptor, namely osteoprotegerin (OPG), a secreted tumor necrosis factor receptor homologue that inhibits osteoclastogenesis and increases bone density in vivo. OPG-Fc binds TRAIL with an affinity of 3.0 nM, which is slightly weaker than the interaction of TRID-Fc or DR5-Fc with TRAIL. OPG inhibits TRAIL-induced apoptosis of Jurkat cells. Conversely, TRAIL blocks the anti-osteoclastogenic activity of OPG. These data suggest potential cross-regulatory mechanisms by OPG and TRAIL.

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CD4 glycoprotein on the surface of T cells helps in the immune response and is the receptor for HIV infection. The structure of a soluble fragment of CD4 determined at 2.3 Å resolution reveals that the molecule has two intimately associated immunoglobulin-like domains. Residues implicated in HIV recognition by analysis of mutants and antibody binding are salient features in domain D1. Domain D2 is distinguished by a variation on the β-strand topologies of antibody domains and by an intra-sheet disulphide bridge.CD4, a cell-surface glycoprotein found primarily on T lymphocytes, is required to shape the T-cell repertoire during thymic development and to permit appropriate activation of mature T cells 1 . T cells that recognize antigens associated with class II major histocompatibility complex (MHC) molecules, mainly T helper cells, express CD4. Evidence is accumulating that CD4 and the T-cell receptor coordinately engage class II molecules on antigenpresenting cells to mediate an efficient cellular immune response, and that engaged CD4 may transmit a signal to an associated cytoplasmic tyrosine kinase, p56 lck .CD4 belongs to the immunoglobulin superfamily of molecules which generally serve in recognition processes 2,3 . The sequence of CD4 4,5 indicates that it consists of a large (~370 residues) extracellular segment composed of four tandem immunoglobulin-like domains, a single transmembrane span, and a short (38 residues) C-terminal cytoplasmic tail. The first domain (D1) shares several features with immunoglobulin variable domains, but the sequence similarities between immunoglobulins and the other extracellular domains (D2, D3 and D4) are more remote.In humans, CD4 can be subverted from its normal immuno-supportive role to become the receptor for infection by the human immunodeficiency virus (HIV) 1,6,7 . Recombinant soluble CD4 proteins bind to the HIV envelope glycoprotein gp120, and can thus inhibit viral infection and virus-mediated cell fusion in vitro (refs 8, 9 and references therein). (refs 21-23 and unpublished results), the main flexibility seems to be at the D2 to D3 junction. We have now crystallized a truncated derivative of CD4 that diffracts well, and here we report its atomic structure. This recombinant fragment 8 as secreted from Chinese hamster ovary (CHO) cells consists of residues 1-183 of human CD4 plus two missense residues, Asp-Thr; and it is unglycosylated. This molecule, which we refer to as D1D2, is as active as sCD4 in binding to gp120 (dissociation constant K d ≃ 3 nM) and retains all antibody epitopes mapped to these domains of CD4 (ref. 8 and unpublished results). Others have crystallized similar fragments from the N-terminal half of sCD4 24,25 and the structure of one is reported in the accompanying paper 25 . HHS Public AccessHere we describe the D1D2 structure in comparison with that of immunoglobulin domains, provide a geometrical definition for HIV recognition sites, and discuss implications of the structure for normal CD4 function and evolution of the immunoglobu...