Structural features of human and mouse FcRL6. (A) Human FcRL6 is a 434–amino acid, type I transmembrane protein of the immunoglobulin superfamily. It contains a leader peptide, encoded by 2 exons, followed by 3 immunoglobulin domains. The protein also contains a cytoplasmic domain with a number of putative signaling motifs. The orthologous gene in mice encodes a type I transmembrane protein highly homologous to the rat protein Gp42. It contains only 2 immunoglobulin domains and lacks a cytoplasmic tail. Patterns within the ovals indicate the sequence homology within the immunoglobulin domains of FcRL6, Gp42, and FcγRI. FcγRI signals through a homodimer of the gamma chain of Fc receptors, which contains a cytoplasmic ITAM. The cDNA and protein sequences for human and mouse FcRL6 are published under GenBank accession numbers AY513661 and EF032497, respectively. (B) The cytoplasmic tail of FcRL6 encodes a series of putative signaling motifs. Most proximal to the membrane is a proline-rich sequence containing a potential SH3-binding PxxP motif (box) followed by 2 YxxV motifs, the second of which is a canonical ITIM (underlined). The last exon encodes a novel cysteine-rich domain containing 2 CxEVxC motifs (shaded) along with several acidic residues that may cooperate for metal binding.