Conformational flexibility and molecular interactions of an archaeal homologue of the Shwachman-Bodian-Diamond syndrome protein

We determined the crystal structure of the SBDS orthologue from Methanothermobacter thermautotrophicus (mthSBDS). This structure shows that SBDS proteins are highly flexible, with the N-terminal FYSH domain and the C-terminal ferredoxin-like domain capable of undergoing substantial rotational adjustments with respect to the central domain. Affinity chromatography identified several proteins from the large ribosomal subunit as possible interacting partners of mthSBDS. Moreover, SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiments, combined with electrophoretic mobility shift assays (EMSA) suggest that mthSBDS does not interact with RNA molecules in a sequence specific manner.It is suggested that functional interactions of SBDS proteins with their partners could be facilitated by rotational adjustments of the N-terminal and the C-terminal domains with respect to the central domain. Examination of the SBDS protein structure and domain movements together with its possible interaction with large ribosomal subunit proteins suggest that these proteins could participate in ribosome function.The Methanothermobacter thermautotrophicus mth685 gene, which encodes the homologue of the Shwachman-Bodian-Diamond syndrome (SBDS) protein, is located in the predicted exosome superoperon [1]. The SBDS proteins are highly conserved [Pfam:PF01172] in archaea and eukaryota [2]. 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 po