Role of Shwachman-Bodian-Diamond syndrome protein in translation machinery and cell chemotaxis: a comparative genomics approach

Abstract

Shwachman-Bodian-Diamond syndrome (SBDS) is linked to a mutation in a single gene. The SBDS proinvolved in RNA metabolism and ribosome-associated functions, but SBDS mutation is primarily linked to a defect in polymorphonuclear leukocytes unable to orient correctly in a spatial gradient of chemoattractants. Results of data mining and comparative genomic approaches undertaken in this study suggest that SBDS protein is also linked to tRNA metabolism and translation initiation. Analysis of crosstalk between translation machinery and cytoskeletal dynamics provides new insights into the cellular chemotactic defects caused by SBDS protein malfunction. The proposed functional interactions provide a new approach to exploit potential targets in the treatment and monitoring of this disease.

Keywords: Shwachman-Bodian-Diamond syndrome; chemotaxis; gene proximity; genomics; tRNA; translation; wybutosine.

Figure 1

Graphical display of the chromosomal neighborhood of sbds genes in archeal genomes. Arrows correspond to open reading frames, same color and number depicts gene orthology. Vertical arrow connects pinned genes (red arrows), ie, orthologs of sbds gene from Methanosarcina barkeri (upper line). Genes encode 1-SBDS protein (AAB90746.1 and its orthologs), 2-probable exosome complex exonuclease 2 (EC 3.1.13.-)/tRNA nucleotidyltransferase, 3-proteasome subunit α (EC 3.4.25.1), 4-probable exosome complex RNA-binding protein 1, 5-large ribosomal subunit protein L37 Ae, 7-large ribosomal subunit protein L15e, 8-ribonuclease P (tRNA processing) protein component 3 (EC 3.1.26.5), 9-ribonuclease P protein component 2 (EC 3.1.26.5), 10-prefoldin, chaperonin cofactor, and 11-predicted exosome subunit containing the IMP4 domain present in small nuclear ribonucleoprotein. 16 kbp regions are shown. Abbreviations: Met. sta.DS, Methanosphaera stadtmanae DSM 3091; Met.the.st- Methanothermobacter thermautotrophicus; Met.mar.S, Methanococcus maripaludis S2; Arc.ful, Archaeoglobus fulgidus DSM 4304; Pyr.aer.st, Pyrobaculum aerophilum str. IM2; Met.bar.st, Methanosarcina barkeri str. Fusaro; Sul.aci.ds, Sulfolobus acidocaldarius DSM 639; Sul.sol. P2, Sulfolobus solfataricus P2; Sul.tok.st, Sulfolobus tokodaii str. 7.

Figure 2

Graphical display of the chromosomal neighborhood of sbds genes in genomes of vertebrates. Arrows correspond to open reading frames encoding: red, Shwachman-Bodian-Diamond syndrome (NM_001008289.1 and pinned orthologs, green), tRNA-YW synthesizing protein (NP_001100607.1 (in Rattus norvegicus) and ortholog, multiple arrows in Xenopus tropicalis correspond to known transcripts), 3-claudin, 4-septin, 5-0610007 L01Rik protein, 6-hypothetical protein, 7-putative dual specificity testis-specific protein kinase 2 (EC 2.7.11.1), and 8-RABX5 (NP_001185988.1). 200 kbp regions are shown. Organisms are R. norvegicus, Mus musculus, Pan troglodytes, X. tropicalis, Gallus gallus, Tetraodon nigroviridis.

Figure 3

Graphical display of the chromosomal neighborhood of sbds genes in fungal genomes. Arrows correspond to open reading frames encoding: 2- SSU ribosomal protein S18e (S13p), 3-carboxypeptidase precursor, and 4- and 5-hypothetical proteins. 100 kbp regions are shown. Organisms are Neurospora crassa, Gibberella zeae, Plasmodium falciparum, and Magnaporthe grisea.

Figure 4

Hypothetical functions of SBDS protein, and their effect on chemotaxis. Clouds represent gene proximity in different groups of organisms, ie, vertebrates (yellow), Ciona intestinalis (blue), and Plasmodium falciparum (purple).