Abstract
BackgroundThe jumonji C (JmjC) domain containing gene 6 (Jmjd6, previously known as phosphatidylserine receptor) has misleadingly been annotated to encode a transmembrane receptor for the engulfment of apoptotic cells. Given the importance of JmjC domain containing proteins in controlling a wide range of diverse biological functions, we undertook a comparative genomic analysis to gain further insights in Jmjd6 gene organisation, evolution, and protein function.ResultsWe describe here a semiautomated computational pipeline to identify and annotate JmjC domain containing proteins. Using a sequence segment N-terminal of the Jmjd6 JmjC domain as query for a reciprocal BLAST search, we identified homologous sequences in 62 species across all major phyla. Retrieved Jmjd6 sequences were used to phylogenetically analyse corresponding loci and their genomic neighbourhood. This analysis let to the identification and characterisation of a bi-directional transcriptional unit compromising the Jmjd6 and 1110005A03Rik genes and to the recognition of a new, before overseen Jmjd6 exon in mammals. Using expression studies, two novel Jmjd6 splice variants were identified and validated in vivo. Analysis of the Jmjd6 neighbouring gene 1110005A03Rik revealed an incident deletion of this gene in two out of three earlier reported Jmjd6 knockout mice, which might affect previously described conflicting phenotypes. To determine potentially important residues for Jmjd6 function a structural model of the Jmjd6 protein was calculated based on sequence conservation. This approach identified a conserved double-stranded β-helix (DSBH) fold and a HxDxnH facial triad as structural motifs. Moreover, our systematic annotation in nine species identified 313 DSBH fold-containing proteins that split into 25 highly conserved subgroups.ConclusionWe give further evidence that Jmjd6 most likely has a function as a nonheme-Fe(II)-2-oxoglutarate-dependent dioxygenase as previously suggested. Further, we provide novel insights into the evolution of Jmjd6 and other related members of the superfamily of JmjC domain containing proteins. Finally, we discuss possibilities of the involvement of Jmjd6 and 1110005A03Rik in an antagonistic biochemical pathway.
Highlights
The jumonji C (JmjC) domain containing gene 6 (Jmjd6, previously known as phosphatidylserine receptor) has misleadingly been annotated to encode a transmembrane receptor for the engulfment of apoptotic cells
The goal of our semiautomated computational pipeline was to identify and systematically analyse all orthologous Jmjd6 loci, all transcripts encoded by the murine and human Jmjd6/JMJD6 loci, the degree and distribution of sequence conservations in Jmjd6 proteins, and their phylogenetic relationship to other JmjC/DSBH domain containing proteins
Extensive validations of each expressed sequence tag (EST) employing Sim4 with our own perlscript for data retrieval, handling, examination and sorting of the results led to a comprehensive analysis of the murine and human Jmjd6/JMJD6 loci and a detailed annotation of all encoded transcripts
Summary
The jumonji C (JmjC) domain containing gene 6 (Jmjd, previously known as phosphatidylserine receptor) has misleadingly been annotated to encode a transmembrane receptor for the engulfment of apoptotic cells. The jumonji C (JmjC)-domain containing proteins are an extending family of redox enzymes that catalyse a wide range of oxidation reactions These proteins are found in all living organisms and are characterised by sharing the highly conserved JmjC domain. Structural studies showed that the JmjC domain has a very characteristic topology It forms a double-stranded β-helix (DSBH) fold, known as jelly-roll motif, that normally consists of eight antiparallel β-strands [6]. This DSBH topology is characteristic for the cupin metalloenzymes [7] and for the JmjC domain containing proteins [3]. This class of enzymes is known as nonheme-Fe(II)-2-oxoglutarate-dependent dioxygenases
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