scholarly journals Shwachman-Diamond Syndrome Protein SBDS Maintains Human Telomeres by Regulating Telomerase Recruitment

Cell Reports ◽  
2018 ◽  
Vol 22 (7) ◽  
pp. 1849-1860 ◽  
Author(s):  
Yi Liu ◽  
Feng Liu ◽  
Yizhao Cao ◽  
Huimin Xu ◽  
Yangxiu Wu ◽  
...  
Keyword(s):  
Shwachman Diamond Syndrome ◽  
Syndrome Protein

Linking Defective Ribosome Maturation to Shwachman-Diamond Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-36-SCI-36
Author(s):  
Alan John Warren
Keyword(s):  
Ribosome Biogenesis ◽  
Conflicts Of Interest ◽  
Ribosomal Subunit ◽  
Protein Translation ◽  
Ribosome Assembly ◽  
Genetic Dissection ◽  
Gtp Hydrolysis ◽  
Shwachman Diamond Syndrome ◽  
Novel Therapeutic Strategies ◽  
Syndrome Protein

Abstract Ribosomes are RNA-protein machines that translate the genetic information encoded by the mRNA template in all living cells. Recent high-resolution structures of the ribosome have revolutionized our understanding of protein translation. However, the mechanisms of ribosome assembly and the surveillance mechanisms that monitor this process and couple it to growth are poorly understood. Causative mutations and deletions of genes involved in ribosome biogenesis define an emerging group of disorders known as the ribosomopathies. Recent work from my laboratory strongly supports the hypothesis that Shwachman-Diamond syndrome (SDS) is a ribosomopathy caused by defective maturation of the large ribosomal subunit. Elucidation of the specific function of the SBDS protein that is deficient in SDS is revealing unexpected new insights that extend our understanding of the mechanisms underlying the late cytoplasmic steps of ribosome assembly and the quality control surveillance pathways that monitor 60S maturation. Genetic dissection of this pathway may inform novel therapeutic strategies for SDS. 1. Wong C.C., Traynor D., Basse N., Kay R.R., Warren A.J. Defective ribosome assembly in Shwachman-Diamond syndrome. Plenary Paper, Blood. 2011 Oct 20;118(16):4305-12. 2. Finch A.J., Hilcenko C., Basse N., Drynan L.F., Goyenechea B., Menne T.F., González Fernández Á., Simpson P., D’Santos C.S., Arends M.J., Donadieu J., Bellanné-Chantelot C., Costanzo M., Boone C., McKenzie A.N., Freund S.M., Warren A.J. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes and Development (2011) 25: 917-929. 3. Menne T.M., Goyenechea B., Sánchez-Puig N., Wong C.C., Tonkin L.M., Ancliff P., Brost R.L., Costanzo M., Boone C. and Warren A.J. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genetics (2007) 39: 486-95. Disclosures: No relevant conflicts of interest to declare.

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

2018 ◽  
Vol 19 (12) ◽  
pp. 4012 ◽  
Author(s):  
Abril Gijsbers ◽  
Diana Montagut ◽  
Alfonso Méndez-Godoy ◽  
Davide Altamura ◽  
Michele Saviano ◽  
...  
Keyword(s):  
Ribosomal Subunit ◽  
Interaction Mechanism ◽  
Elongation Factor ◽  
Missense Mutations ◽  
Molecular Alterations ◽  
X Ray Scattering ◽  
Genes Encoding ◽  
Initial Interaction ◽  
Shwachman Diamond Syndrome ◽  
Syndrome Protein

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.

scholarly journals Structural dynamics of the yeast Shwachman-Diamond syndrome protein (Sdo1) on the ribosome and its implication in the 60S subunit maturation

2016 ◽  
Vol 7 (3) ◽  
pp. 187-200 ◽  
Author(s):  
Chengying Ma ◽  
Kaige Yan ◽  
Dan Tan ◽  
Ningning Li ◽  
Yixiao Zhang ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Shwachman Diamond Syndrome ◽  
Syndrome Protein

scholarly journals Ataluren-driven restoration of Shwachman-Bodian-Diamond syndrome protein function in Shwachman-Diamond syndrome bone marrow cells

2018 ◽  
Vol 93 (4) ◽  
pp. 527-536 ◽  
Author(s):  
Valentino Bezzerri ◽  
Donatella Bardelli ◽  
Jacopo Morini ◽  
Antonio Vella ◽  
Simone Cesaro ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Protein Function ◽  
Bone Marrow Cells ◽  
Shwachman Diamond Syndrome ◽  
Syndrome Protein ◽  
Marrow Cells

Impaired growth, hematopoietic colony formation, and ribosome maturation in human cells depleted of Shwachman-Diamond syndrome protein SBDS

2012 ◽  
Vol 60 (2) ◽  
pp. 281-286 ◽  
Author(s):  
Gulay Sezgin ◽  
Adrianna L. Henson ◽  
Abdallah Nihrane ◽  
Sharon Singh ◽  
Max Wattenberg ◽  
...  
Keyword(s):  
Colony Formation ◽  
Human Cells ◽  
Shwachman Diamond Syndrome ◽  
Syndrome Protein

Spatial control of actin-based motility through plasmalemmal PtdIns(4,5)P2-rich raft assemblies.

2005 ◽  
Vol 72 ◽  
pp. 119-127 ◽  
Author(s):  
Tamara Golub ◽  
Caroni Pico
Keyword(s):  
Protein Kinase ◽  
Cell Surface ◽  
Actin Cytoskeleton ◽  
Lipid Rafts ◽  
Patch Clustering ◽  
Pkc Protein Kinase C ◽  
Membrane Bound ◽  
And Function ◽  
Cytoskeleton Dynamics ◽  
Syndrome Protein

The interactions of cells with their environment involve regulated actin-based motility at defined positions along the cell surface. Sphingolipid- and cholesterol-dependent microdomains (rafts) order proteins at biological membranes, and have been implicated in most signalling processes at the cell surface. Many membrane-bound components that regulate actin cytoskeleton dynamics and cell-surface motility associate with PtdIns(4,5)P2-rich lipid rafts. Although raft integrity is not required for substrate-directed cell spreading, or to initiate signalling for motility, it is a prerequisite for sustained and organized motility. Plasmalemmal rafts redistribute rapidly in response to signals, triggering motility. This process involves the removal of rafts from sites that are not interacting with the substrate, apparently through endocytosis, and a local accumulation at sites of integrin-mediated substrate interactions. PtdIns(4,5)P2-rich lipid rafts can assemble into patches in a process depending on PtdIns(4,5)P2, Cdc42 (cell-division control 42), N-WASP (neural Wiskott-Aldrich syndrome protein) and actin cytoskeleton dynamics. The raft patches are sites of signal-induced actin assembly, and their accumulation locally promotes sustained motility. The patches capture microtubules, which promote patch clustering through PKA (protein kinase A), to steer motility. Raft accumulation at the cell surface, and its coupling to motility are influenced greatly by the expression of intrinsic raft-associated components that associate with the cytosolic leaflet of lipid rafts. Among them, GAP43 (growth-associated protein 43)-like proteins interact with PtdIns(4,5)P2 in a Ca2+/calmodulin and PKC (protein kinase C)-regulated manner, and function as intrinsic determinants of motility and anatomical plasticity. Plasmalemmal PtdIns(4,5)P2-rich raft assemblies thus provide powerful organizational principles for tight spatial and temporal control of signalling in motility.

Shwachman–Diamond syndrome: Clinical manifestations and molecular genetics

2007 ◽  
Vol 148 (11) ◽  
pp. 513-519
Author(s):  
Melinda Erdős ◽  
László Maródi
Keyword(s):  
Molecular Genetics ◽  
Clinical Manifestations ◽  
Shwachman Diamond Syndrome

A Shwachman–Diamond-szindróma ritka, autoszomális recesszív öröklődésmenetű primer immunhiánybetegség, amelyre exocrin pancreaselégtelenség, metaphysealis dysostosis, növekedési retardáció, csontvelő-diszfunkció és visszatérő fertőzések jellemzők. A közleményben a szerzők ismertetik a betegség klinikumát, laboratóriumi eltéréseit, összefoglalják a kórkép molekuláris patomechanizmusával kapcsolatos ismereteket és kezelésének lehetőségeit. Bemutatják egy Magyarországon elsőként diagnosztizált Shwachman–Diamond-szindrómában szenvedő gyermek kórtörténetét, akinek alapbetegségét genetikai vizsgálattal igazolták. A klinikai képet congenitalis neutropenia, az exocrin pancreaselégtelenség következtében kialakuló súlyos malabsorptiós szindróma és visszatérő, gennyes bőr-, illetve alsó- és felső légúti fertőzések jellemezték. A Shwachman–Diamond-szindróma génjén két új, az irodalomban korábban még nem leírt mutációt (c.362A > C, p.N121T és c.523C > T, p.R175W) találtak. A beteg gyermek születendő testvérében praenatalis genetikai vizsgálatot végeztek, amely hordozó állapotot igazolt. Ennek alapján az anya dönthetett a terhesség kihordásáról.

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