Ribosome maturation protein SBDS is a protein that in humans is encoded by the SBDSgene.[1] 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.[2] This gene encodes a member of a highly conserved protein family that exists from archaea to vertebrates and plants.
The encoded protein may function in RNA metabolism.[2] The precise function of the SBDS protein is not known but it appears to play an important role in ribosome function or assembly.[3]Knockdown of SBDS expression results in increased apoptosis in erythroid cells undergoing differentiation due to elevated ROS levels. Hence SBDS is critical for normal erythropoiesis.[4]
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.[1][5]
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.[3]
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.[5]
Structure
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.[5]
SBDS central domain
Function
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.[5]
Structure
This domain contains a very common structure, the winged helix-turn-helix.[5]
Members of this family are thought to play a role in RNA metabolism.[5] However, its precise function remains to be elucidated. Furthermore, its structure makes it very difficult to predict the protein domain's function.[5]
Structure
The structure of the C-terminal domain contains a ferredoxin-like fold[7] This structure has a four-stranded beta-sheet with two helices on one side.[5]
Clinical significance
Mutations within this gene are associated with Shwachman-Bodian-Diamond syndrome.[2] 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).[3]
References
↑ 1.01.11.2Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM (Jan 2003). "Mutations in SBDS are associated with Shwachman-Diamond syndrome". Nat Genet. 33 (1): 97–101. doi:10.1038/ng1062. PMID12496757.
↑Sen S, Wang H, Nghiem CL, Zhou K, Yau J, Tailor CS, Irwin MS, Dror Y (December 2011). "The ribosome-related protein, SBDS, is critical for normal erythropoiesis". Blood. 118 (24): 6407–17. doi:10.1182/blood-2011-02-335190. PMID21963601.
↑ 5.05.15.25.35.45.55.65.7Savchenko A, Krogan N, Cort JR, Evdokimova E, Lew JM, Yee AA, Sánchez-Pulido L, Andrade MA, Bochkarev A, Watson JD, Kennedy MA, Greenblatt J, Hughes T, Arrowsmith CH, Rommens JM, Edwards AM (May 2005). "The Shwachman-Bodian-Diamond syndrome protein family is involved in RNA metabolism". J. Biol. Chem. 280 (19): 19213–20. doi:10.1074/jbc.M414421200. PMID15701634.
↑Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM (January 2003). "Mutations in SBDS are associated with Shwachman-Diamond syndrome". Nat. Genet. 33 (1): 97–101. doi:10.1038/ng1062. PMID12496757.
Popovic M, Goobie S, Morrison J, et al. (2002). "Fine mapping of the locus for Shwachman-Diamond syndrome at 7q11, identification of shared disease haplotypes, and exclusion of TPST1 as a candidate gene". Eur. J. Hum. Genet. 10 (4): 250–8. doi:10.1038/sj.ejhg.5200798. PMID12032733.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID14702039.
Nakashima E, Mabuchi A, Makita Y, et al. (2004). "Novel SBDS mutations caused by gene conversion in Japanese patients with Shwachman-Diamond syndrome". Hum. Genet. 114 (4): 345–8. doi:10.1007/s00439-004-1081-2. PMID14749921.
Woloszynek JR, Rothbaum RJ, Rawls AS, et al. (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.
Kawakami T, Mitsui T, Kanai M, et al. (2005). "Genetic analysis of Shwachman-Diamond syndrome: phenotypic heterogeneity in patients carrying identical SBDS mutations". Tohoku J. Exp. Med. 206 (3): 253–9. doi:10.1620/tjem.206.253. PMID15942154.
Boocock GR, Marit MR, Rommens JM (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.
Erdos M, Alapi K, Balogh I, et al. (2007). "Severe Shwachman-Diamond syndrome phenotype caused by compound heterozygous missense mutations in the SBDS gene". Exp. Hematol. 34 (11): 1517–21. doi:10.1016/j.exphem.2006.06.009. PMID17046571.
Wang Y, Yagasaki H, Hama A, et al. (2007). "Mutation of SBDS and SH2D1A is not associated with aplastic anemia in Japanese children". Haematologica. 92 (11): 1573. doi:10.3324/haematol.11568. PMID18024409.