Sanquin Research and Landsteiner Laboratory of the Academic Medical Center, Department of Blood Cell Research, University of Amsterdam, Amsterdam, The Netherlands.
PLoS One. 2011;6(6):e20727. doi: 10.1371/journal.pone.0020727. Epub 2011 Jun 13.
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.
Shwachman-Diamond 综合征（SDS）是一种由 SBDS 基因突变引起的罕见遗传性疾病。造血缺陷、外分泌胰腺功能障碍和身材矮小是最突出的临床特征。为了了解广泛表达的 SBDS 蛋白的分子特性，我们通过活细胞成像技术研究了其细胞内定位和迁移。我们观察到全长 SBDS 蛋白定位于细胞核和细胞质中，而与患者相关的截断 SBDS 蛋白同工型主要定位于细胞核。这些与患者相关的 SBDS 蛋白的核质转运也受到干扰。进一步研究一系列 SBDS 突变蛋白表明，三个不同的基序决定了 SBDS 蛋白的细胞内迁移。C 端结构域中的一个 sumoylation 基序在患者 SBDS 蛋白中缺失，被发现对细胞内运动起着关键作用。我们的结构-功能分析为 SBDS 蛋白的定位和迁移提供了新的见解，并表明与患者相关的突变蛋白在分子特性上发生了改变，这可能导致 SDS 患者观察到的临床特征。
