Hu‐K4 is a human protein homologous to the K4L protein of vaccinia virus. Due to the presence of two HKD motifs, Hu‐K4 was assigned to the family of Phospholipase D proteins although so far no catalytic activity has been shown. The Hu‐K4 mRNA is found in many human organs with highest expression levels in the central nervous system. We extended the ORF of Hu‐K4 to the 5′ direction. As a consequence the protein is 53 amino acids larger than originally predicted, now harbouring a putative transmembrane domain. The exon/intron structure of the Hu‐K4 gene reveals extensive alternative splicing in the 5′ untranslated region. Due to the absence of G/C‐rich regions and upstream ATG codons, the mRNA isoform in brain may be translated with higher efficacy leading to a high Hu‐K4 protein concentration in this tissue. Using a specific antiserum produced against Hu‐K4 we found that Hu‐K4 is a membrane‐bound protein colocalizing with protein disulfide isomerase, a marker of the endoplasmic reticulum. Glycosylation of Hu‐K4 as shown by treatment with peptide N‐glycosidase F or tunicamycin indicates that Hu‐K4 has a type 2 transmembrane topology.

Background: Based on sequence similarity, the superfamily of G protein-coupled receptors (GPRs) can be subdivided into several subfamilies, the members of which often share similar ligands. The sequence data provided by the human genome project allows us to identify new GPRs by in silico homology screening, and to predict their ligands.

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