The Methanothermobacter thermautotrophicus mth685 gene, which encodes the homologue of the Shwachman-Bodian-Diamond syndrome (SBDS) protein, is located in the predicted exosome superoperon . The SBDS proteins are highly conserved [Pfam:PF01172] in archaea and eukaryota . Mutations of the human SBDS gene are associated with the condition known as Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder with clinical features including hematological and skeletal abnormalities and also exocrine pancreatic insufficiency [OMIM:260400]. The most common mutations associated with SDS include the polypeptide chain truncation K62X caused by the introduction of an in-frame stop codon (183–184TA → CT mutation) and a donor splicing site mutation, 258+2T → C, which causes premature truncation of the encoded protein by frameshift (84Cfs3). In addition, several point mutations across the entire sequence of the protein are also associated with SDS [2–6]
Experiments with YLR022c (SDO1), the yeast homologue of the SBDS protein, have shown that its mutations C31W, L71P and I87S affect the protein stability . SDO1 is a non-essential protein  present in the cytoplasm, nucleus and nucleolus of the cell [9, 10], which is required for G1 cell cycle progression . This protein has been found to interact with 13 different proteins by yeast two-hybrid screening, tandem affinity purification (TAP) and biochemical studies. The set of identified interaction partners include proteins involved in rRNA processing, ribosomal biogenesis, RNA transport, as well as exoribonucleases and two serine/threonine protein kinases [9, 12–14]. However, different methods pointed to different interacting partners of SDO1, and none of the hits were retrieved by more than one study. Recently, SDO1 has been shown to contribute to the export of pre-60S ribosomal particles to the cytoplasm by facilitating the release and recycling of the nucleolar shuttling factor Tif6 from the cytoplasmic pre-60S ribosomes . A role in ribosomal biogenesis is further supported by the observed interaction of human SBDS with nucleophosmin (NPM) and Nip7 [15, 16].
Other studies have suggested that SBDS proteins might be involved in RNA metabolism. This hypothesis is supported by both its genomic context and by experimental evidence. In particular, the archaeal SBDS orthologues are located in a superoperon that encodes, among others, several proteins of the exosome particle, a conserved multiprotein complex involved in RNA processing and degradation in eukaryotes and archaea [1, 17]. Furthermore, the SBDS orthologues in the plants Arabidopsis thaliana and Oryza sativa contain an extended C-terminal region with putative RNA-binding domains, namely U1-type zinc fingers [7, 18].
Hitherto, the only structural information on SBDS proteins is based on two virtually identical X-ray structures of an archaeal orthologue of SBDS from Archaeoglobus fulgidus (afSBDS) [7, 13]. These studies showed that the SBDS protein contains three domains. The N-terminal FYSH domain (residues 1–86) displays an α/β topology with a novel fold, the middle domain (87–160) has a three-helix bundle fold, and the C-terminal domain (161–234) exhibits a ferredoxin-like fold that is commonly found in proteins with various functions, including numerous RNA binding proteins. Although the protein has an extended tripartite architecture, the extent of its conformational variability was not fully apparent from these structural studies, and its electrostatic or RNA-binding properties have not been characterized either.
Here we address these issues by determining the X-ray structure and probing the RNA and protein-binding capabilities of the SBDS orthologue from the archaeon M. thermautotrophicus (mthSBDS). We show that SBDS proteins are highly flexible and can readjust the relative positions of their N-terminal and C-terminal domains in relation to the middle domain. We also present the results of affinity chromatography and SELEX experiments aimed at identifying protein and RNA molecules that interact with the mthSBDS. These data show that the mthSBDS protein can interact with several ribosomal proteins and suggest that it does not interact with a specific RNA sequence. Finally, we discuss the potential functional implications of the flexibility, the shape and the surface charge distribution of mthSBDS.