Ribosome maturation protein SBDS is a protein that in humans is encoded by the SBDSgene.[5] An alternative transcript has been described, but its biological nature has not been determined. This gene has a closely linked pseudogene that is distally located.[6] This gene encodes a member of a highly conserved protein family that exists in all archaea and eukaryotes.
The encoded protein plays an essential role in ribosome biogenesis. SBDS interacts with elongation factor-like GTPase 1 (Efl1) to disassociate eukaryotic initiation factor 6 (eIF6) from the late cytoplasmic pre-60S ribosomal subunit allowing assembly of the 80S.[6] Dynamic rotation of the SBDS protein in the ribosomal P site is coupled to a conformational switch in EFL1 that promotes eIF6 displacement through competition for an overlapping binding site on the 60S ribosomal subunit.[7] Yeast SBDS ortholog, Sdo1, functions within a pathway containing Efl1 to facilitate the release and recycling of the nucleolar shuttling factor Tif6 (yeast eIF6 ortholog) from late cytoplasmic pre-60S ribosomal subunit.[8]Knockdown of SBDS expression results in increased apoptosis in erythroid cells undergoing differentiation due to elevated ROS levels.[9] Hence SBDS is critical for normal erythropoiesis.[10]
This family is highly conserved in species ranging from archaea to vertebrates and plants. The family contains several Shwachman-Bodian-Diamond syndrome (SBDS) proteins from both mouse and humans. Shwachman-Diamond syndrome is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. Members of this family play a role in RNA metabolism.[5][11]
A number of uncharacterised hydrophilic proteins of about 30 kDa share regions of similarity. These include,
The SBDS protein contains three domains, an N-terminal conserved FYSH domain, central helical domain and C-terminal domain containing an RNA-binding motif.[9]
This protein domain appears to be very important, since mutations in this domain are usually the cause of Shwachman-Bodian-Diamond syndrome. It shares distant structural and sequence homology to a protein named YHR087W found in the yeast Saccharomyces cerevisiae. The protein YHR087W is involved in RNA metabolism, so it is probable that the SBDS N-terminal domain has the same function.[11]
The N-terminal domains contains a novel mixed alphabeta fold, four beta-strands, and four alpha-helices arranged as a three beta stranded anti-parallel-sheet.[11]
Central domain
The function of this protein domain has been difficult to elucidate. It is possible that it has a role in binding to DNA or RNA. Protein binding to form a protein complex is also another possibility. It has been difficult to infer the function from the structure since this particular domain structure is found in archea.[11]
Members of this family are thought to play a role in RNA metabolism.[11] However, its precise function remains to be elucidated. Furthermore, its structure makes it very difficult to predict the protein domain's function.[11]
The structure of the C-terminal domain contains a ferredoxin-like fold[12] This structure has a four-stranded beta-sheet with two helices on one side.[11]
Clinical significance
Mutations within this gene are associated with Shwachman-Bodian-Diamond syndrome.[6] The two most common mutations associated with this syndrome are at positions 183–184 (TA→CT) resulting in a premature stop-codon (K62X) and a frameshift mutation at position 258 (2T→C) resulting in a stopcodon (C84fsX3).[9]
Nakashima E, Mabuchi A, Makita Y, Masuno M, Ohashi H, Nishimura G, Ikegawa S (March 2004). "Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome". Human Genetics. 114 (4): 345–8. doi:10.1007/s00439-004-1081-2. PMID14749921. S2CID30492406.
Woloszynek JR, Rothbaum RJ, Rawls AS, Minx PJ, Wilson RK, Mason PJ, etal. (December 2004). "Mutations of the SBDS gene are present in most patients with Shwachman-Diamond syndrome". Blood. 104 (12): 3588–90. doi:10.1182/blood-2004-04-1516. PMID15284109. S2CID43717208.
Boocock GR, Marit MR, Rommens JM (June 2006). "Phylogeny, sequence conservation, and functional complementation of the SBDS protein family". Genomics. 87 (6): 758–71. doi:10.1016/j.ygeno.2006.01.010. PMID16529906.
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