title: Altered intracellular localization and mobility of SBDS protein upon mutation in Shwachman-Diamond syndrome.
abstract: Shwachman-Diamond Syndrome (SDS) is a rare inherited disease caused by mutations in the SBDS gene. Hematopoietic defects, exocrine pancreas dysfunction and short stature are the most prominent clinical features. To gain understanding of the molecular properties of the ubiquitously expressed SBDS protein, we examined its intracellular localization and mobility by live cell imaging techniques. We observed that SBDS full-length protein was localized in both the nucleus and cytoplasm, whereas patient-related truncated SBDS protein isoforms localize predominantly to the nucleus. Also the nucleo-cytoplasmic trafficking of these patient-related SBDS proteins was disturbed. Further studies with a series of SBDS mutant proteins revealed that three distinct motifs determine the intracellular mobility of SBDS protein. A sumoylation motif in the C-terminal domain, that is lacking in patient SBDS proteins, was found to play a pivotal role in intracellular motility. Our structure-function analyses provide new insight into localization and motility of the SBDS protein, and show that patient-related mutant proteins are altered in their molecular properties, which may contribute to the clinical features observed in SDS patients.
authors.affiliation: Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, Department of Blood Cell Research, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Orelio
authors.forename: Renée M
authors.initials: RM
authors.lastname: van der Sluis
authors.forename: Paul
authors.initials: P
authors.lastname: Verkuijlen
authors.forename: Micha
authors.initials: M
authors.lastname: Nethe
authors.forename: Peter L
authors.initials: PL
authors.lastname: Hordijk
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D021581:Active Transport, Cell Nucleus; D020816:Amino Acid Motifs; D001855:Bone Marrow Diseases / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D010188:Exocrine Pancreatic Insufficiency / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism*; D008068:Lipomatosis; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D021381:Protein Transport; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000081003:Shwachman-Diamond Syndrome; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; C470521:SBDS protein, human; D049452:Green Fluorescent Proteins