Hematologically important mutations: Shwachman–Diamond syndrome

Costa, Elı́sio; Santos, Rosário

doi:10.1016/j.bcmd.2007.07.008

Cited by 11 publications

(7 citation statements)

References 13 publications

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“…Most of the disease-related mutations in human SBDS 46 localize to the N-terminal domain and are in close proximity to the RNA binding region. The majority of the reported mutations occur in charged residues of the domain, which could perturb the RNA interaction by changing the basic character of the surface patch, as is the case for R19Q, K33E, and K67E.…”

Section: Mutations In Human Sbds and Implication On Rna Interactionmentioning

confidence: 99%

Structure, Dynamics, and RNA Interaction Analysis of the Human SBDS Protein

Oliveira

Sforça

Blumenschein

et al. 2010

Journal of Molecular Biology

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Shwachman-Bodian-Diamond syndrome is an autosomal recessive genetic syndrome with pleiotropic phenotypes, including pancreatic deficiencies, bone marrow dysfunctions with increased risk of myelodysplasia or leukemia, and skeletal abnormalities. This syndrome has been associated with mutations in the SBDS gene, which encodes a conserved protein showing orthologs in Archaea and eukaryotes. The Shwachman-Bodian-Diamond syndrome pleiotropic phenotypes may be an indication of different cell type requirements for a fully functional SBDS protein. RNA-binding activity has been predicted for archaeal and yeast SBDS orthologs, with the latter also being implicated in ribosome biogenesis. However, full-length SBDS orthologs function in a species-specific manner, indicating that the knowledge obtained from model systems may be of limited use in understanding major unresolved issues regarding SBDS function, namely, the effect of mutations in human SBDS on its biochemical function and the specificity of RNA interaction. We determined the solution structure and backbone dynamics of the human SBDS protein and describe its RNA binding site using NMR spectroscopy. Similarly to the crystal structures of Archaea, the overall structure of human SBDS comprises three well-folded domains. However, significant conformational exchange was observed in NMR dynamics experiments for the flexible linker between the N-terminal domain and the central domain, and these experiments also reflect the relative motions of the domains. RNA titrations monitored by heteronuclear correlation experiments and chemical shift mapping analysis identified a classic RNA binding site at the N-terminal FYSH (fungal, Yhr087wp, Shwachman) domain that concentrates most of the mutations described for the human SBDS.

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Section: Mutations In Human Sbds and Implication On Rna Interactionmentioning

confidence: 99%

Structure, Dynamics, and RNA Interaction Analysis of the Human SBDS Protein

Oliveira

Sforça

Blumenschein

et al. 2010

Journal of Molecular Biology

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“…Most patients harbour the biallelic pathogenic variants c.183_184TA > CT (K62X) and c.258 + 2T > C (C84fsX3), which result in truncated forms of the protein within its first domain [3]. Less common mutations have also been reported throughout the gene including nonsense mutations, missense mutations, small deletions, indel conversions and splice-site mutations [3,4,5,6,7]. The SBDS gene is located in chromosome 7q11, and encodes for a protein structurally organized into three highly conserved domains [8,9,10].…”

Section: Introductionmentioning

confidence: 99%

Interaction of the GTPase Elongation Factor Like-1 with the Shwachman-Diamond Syndrome Protein and Its Missense Mutations

Gijsbers

Montagut

Méndez-Godoy

et al. 2018

IJMS

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The Shwachman-Diamond Syndrome (SDS) is a disorder arising from mutations in the genes encoding for the Shwachman-Bodian-Diamond Syndrome (SBDS) protein and the GTPase known as Elongation Factor Like-1 (EFL1). Together, these proteins remove the anti-association factor eIF6 from the surface of the pre-60S ribosomal subunit to promote the formation of mature ribosomes. SBDS missense mutations can either destabilize the protein fold or affect surface epitopes. The molecular alterations resulting from the latter remain largely unknown, although some evidence suggest that binding to EFL1 may be affected. We further explored the effect of these SBDS mutations on the interaction with EFL1, and showed that all tested mutations disrupted the binding to EFL1. Binding was either severely weakened or almost abolished, depending on the assessed mutation. In higher eukaryotes, SBDS is essential for development, and lack of the protein results in early lethality. The existence of patients whose only source of SBDS consists of that with surface missense mutations highlights the importance of the interaction with EFL1 for their function. Additionally, we studied the interaction mechanism of the proteins in solution and demonstrated that binding consists of two independent and cooperative events, with domains 2–3 of SBDS directing the initial interaction with EFL1, followed by docking of domain 1. In solution, both proteins exhibited large flexibility and consisted of an ensemble of conformations, as demonstrated by Small Angle X-ray Scattering (SAXS) experiments.

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“…2 Other rarer mutations were recently reviewed by Costa and Santos. 4 The SBDS gene, highly conserved throughout evolution, encodes a 250 amino-acid protein with no homology to other proteins of known function. This protein was shown to be relevant for ribosome biogenesis and, more recently, also for stabilization of the mitotic spindle.…”

Section: Introductionmentioning

confidence: 99%