Structural and Mutational Analysis of the SBDS Protein Family

Shammas, Camille; Menne, Tobias; Hilcenko, Christine; Michell, Stephen R.; Goyenechea, Beatriz; Boocock, Graeme R.B.; Durie, Peter R.; Rommens, Johanna M.; Warren, Alan J.

doi:10.1074/jbc.m414656200

Cited by 106 publications

(45 citation statements)

References 42 publications

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“…Recent studies on the SBDS orthologs suggested that SBDS is involved in RNA processing and ribosome biogenesis [12,13]. If these postulated functions of SBDS account for the accelerated apoptosis in SBDS-deficient cells, one would expect that inhibition of either RNA transcription or protein synthesis would results in marked cell death.…”

Section: Discussionmentioning

confidence: 99%

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SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane

et al. 2008

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Shwachman-Diamond syndrome (SDS) is an inherited disorder characterized by reduced cellularity in the bone marrow and exocrine pancreas. Most patients have mutations in the SBDS gene, whose functions are unknown. We previously showed that cells deficient in the SBDS protein are characterized by accelerated apoptosis and Fas hypersensitivity, suggesting that the protein might play an important role in Fas-mediated apoptosis. To study the mechanism of Fas hypersensitivity, we compared shRNA-mediated SBDS-knockdown HeLa cells and SDS marrow CD34+ cells for their sensitivity to several groups of apoptosis inducers. Marked hypersensitivity was noticed in response to Fas stimulation, but not to tumor necrosis factor-alpha, DNA-damaging agents, transcription inhibition or protein synthesis inhibition. To identify the Fas signaling factors that cause hypersensitivity, we analyzed the expression of the pathway's proteins. We found that Fas accumulated at the plasma membrane in SBDS-knockdown cells with corresponding expression of Fas transcript 1, the main Fas transcript which contains both the transmembrane domain and the death domain. However, the total levels of Fas protein and mRNA were comparable to controls, and Fas internalization occurred normally. Expression of FADD, caspase-8 and -3 were not elevated and the pathway inhibitors: ERK, c-FLIP and XIAP were not decreased. These results suggest that SBDS loss results in abnormal accumulation of Fas at the plasma membrane, where it sensitizes the cells to stimulation by Fas ligand.

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Section: Discussionmentioning

confidence: 99%

“…The functions of the SBDS protein are unknown; however, various data suggest a role of SBDS in regulating apoptosis, [7,8] ribosomal biogenesis [9][10][11][12][13] and chemotaxis [14][15][16]. Since SDS marrows are hypocellular, [1,2,17] we previously asked whether SDS marrow progenitors undergo accelerated apoptosis.…”

Section: Introductionmentioning

confidence: 99%

SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane

et al. 2008

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“…It has been reported that SBDS is composed of three domains with weak contacts among them [8,9,10]. As SBDS family proteins share a similar structure and sequence, ScSBDS is expected to consist of domain I (Met1 -Gln94), domain II (Leu95 -Ala172), and domain III (Lys173 -Asn250) (Fig.…”

Section: Identification Of the Binding Region In Sbdsmentioning

confidence: 99%

“…S1), and missense mutations of SBDS associated with Shwachman-Diamond syndrome were identified in all three domains [8]. Nuclear magnetic resonance (NMR) spectroscopy identified domain I of SBDS as an RNA binding site [10].…”

Section: Introductionmentioning

confidence: 99%

“…The removal of Tif6-the yeast homolog of mammalian eukaryotic translation initiation factor 6 (eIF6)-is critical for late cytoplasmic maturation of the 60S ribosomal subunit [5]. Tif6 acts as a ribosomal anti-association factor, which binds to the pre-60S subunit to inhibit subunit joining by steric hindrance [6,7,8]. Therefore, dissociation of Tif6 from pre-60S ribosome is essential for enabling assembly into the 80S subunit.…”

Section: Introductionmentioning

confidence: 99%

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Direct interaction between EFL1 and SBDS is mediated by an intrinsically disordered insertion domain

Asano¹,

Atsuumi²,

Nakamura³

et al. 2014

Biochemical and Biophysical Research Communications

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HIGHLIGHTS• The interaction between EFL1 and SBDS was elucidated.• EFL1 binds directly to SBDS with an association constant of 1.27×10 7 M -1 .• The interaction is governed by the insertion domain of EFL1 and domain II -III of SBDS.• The insertion domain of EFL1 acts as an intrinsically disordered domain.• Roles of each domain of EFL1 and SBDS in Tif6 release are proposed. 2 ABSTRACTRemoval of anti-association factor, Tif6 (eIF6), by elongation factor-like 1 (EFL1) and Shwachman-Bodian-Diamond syndrome (SBDS) protein is a critical step in the late stage of ribosome maturation. Although EFL1 is known to have GTPase activity that is stimulated by SBDS, how they cooperatively trigger dissociation of Tif6 from the ribosome remains to be elucidated. In the present study, the interaction between EFL1 and SBDS was analyzed by size exclusion chromatography, gel shift assay, and isothermal titration calorimetry (ITC).The results showed that EFL1 interacted directly with SBDS. ITC experiments using domaintruncated mutants showed that the interaction between EFL1 and SBDS is governed by the insertion domain of EFL1 and domains II -III of SBDS. Circular dichroism spectroscopyshowed that the insertion domain of EFL1 has a random structure in the absence of SBDS, whereas the disadvantageous entropy change observed on ITC suggested a fixed conformation coupled with complex formation with SBDS. Based on these observations together with those reported previously, we propose roles of EFL1 and SBDS in ribosomal maturation.3

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Novel myopathy in a newborn with Shwachman–Diamond syndrome and review of neonatal presentation

Topa

Tulinius

Oldfors

et al. 2016

American J of Med Genetics Pt A

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Shwachman-Diamond-Bodian syndrome (SDS) is a pleiotropic disorder in which the main features are bone marrow dysfunction and pancreatic insufficiency. Skeletal changes can occur, and in rare cases manifest as severe congenital thoracic dystrophy. We report a newborn boy with asphyxia, narrow thorax, and severe hypotonia initially suggesting a neuromuscular disease. The muscle biopsy showed myopathic changes with prominent variability in muscle fiber size and abnormal expression of developmental isoforms of myosin. The myofibrils showed focal loss and disorganization of myofilaments, and thickening of the Z-discs including some abortive nemaline rods. The boy became permanently dependent on assisted ventilation. Pancreatic insufficiency was subsequently diagnosed, explaining the malabsorption and failure to thrive. Except transitory thrombocytopenia and leukopenia, no major hematological abnormalities were noted. He had bilateral nephrocalcinosis with preserved renal function. Transitory liver dysfunction with elevated transaminase levels and parenchymal changes on ultrasound were registered. The clinical diagnosis was confirmed by detection of compound heterozygous mutations in SBDS using whole-exome sequencing: a recurrent intronic mutation causing aberrant splicing (c.258+2T>C) and a novel missense variant in a highly conserved codon (c.41A>G, p.Asn14Ser), considered to be damaging for the protein structure by in silico prediction programs. The carrier status of the parents has been confirmed. This case illustrates the challenges in differential diagnosis of pronounced neonatal hypotonia with asphyxia and highlights the muscular involvement in SDS. To our knowledge, this is the first report of myopathy evidenced in a patient with clinically and molecularly confirmed SDS.

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Structural and Mutational Analysis of the SBDS Protein Family

Cited by 106 publications

References 42 publications

SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane

SBDS-deficiency results in specific hypersensitivity to Fas stimulation and accumulation of Fas at the plasma membrane

Direct interaction between EFL1 and SBDS is mediated by an intrinsically disordered insertion domain

Novel myopathy in a newborn with Shwachman–Diamond syndrome and review of neonatal presentation

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