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.
| Original language | English |
|---|---|
| Pages (from-to) | e20727 |
| Journal | PLoS ONE |
| Volume | 6 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2011 |
Cite this
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Altered intracellular localization and mobility of SBDS protein upon mutation in Shwachman-Diamond syndrome. / Orelio, Claudia; van der Sluis, Renée M; Verkuijlen, Paul; Nethe, Micha; Hordijk, Peter L; van den Berg, Timo K; Kuijpers, Taco W.
In: PLoS ONE, Vol. 6, No. 6, 2011, p. e20727.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Altered intracellular localization and mobility of SBDS protein upon mutation in Shwachman-Diamond syndrome
AU - Orelio, Claudia
AU - van der Sluis, Renée M
AU - Verkuijlen, Paul
AU - Nethe, Micha
AU - Hordijk, Peter L
AU - van den Berg, Timo K
AU - Kuijpers, Taco W
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Active Transport, Cell Nucleus
KW - Amino Acid Motifs
KW - Bone Marrow Diseases/genetics
KW - Cell Nucleus/metabolism
KW - Exocrine Pancreatic Insufficiency/genetics
KW - Green Fluorescent Proteins/metabolism
KW - HeLa Cells
KW - Humans
KW - Intracellular Space/metabolism
KW - Lipomatosis
KW - Models, Biological
KW - Mutant Proteins/metabolism
KW - Mutation/genetics
KW - Protein Transport
KW - Proteins/genetics
KW - Recombinant Fusion Proteins/metabolism
KW - Subcellular Fractions/metabolism
U2 - 10.1371/journal.pone.0020727
DO - 10.1371/journal.pone.0020727
M3 - Article
VL - 6
SP - e20727
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 6
ER -