Studies on Perxisome Biogenesis and Function of Pex1p

Pex1p过氧化物酶体的生物发生及功能研究

• 批准号: 11680608
• 负责人: TAMURA Shigehiko
• 金额: $ 2.3万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680608/
• 关键词: peroxisome; peroxisome biogenesis disorders; CHO cell mutants; peroxin; membrane prorein; AAA protein; pathogenic genes; protein-protein interaction; 変異部位解析; peroxisome; peroxisome biogenesis disorders; CHO cell mutants; peroxin; membrane prorein; AAA protein; pathogenic genes; protein-protein interaction; 変異部位解析

With the support of this Grants-in Aid for Scientific Research 11680608, we obtained following findings :The peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (ZS) and neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), are fatal autosomal recessive diseases caused by defects in peroxisome assembly as well as malfunction of peroxisomes, where 12 genotypes have been reported. ZS patients manifest the severest clinical and biochemical abnormalities, while those with NALD and IRD show the less severity and the mildest features, respectively. However, little attention has been paid to determining at the molecular level the phenotype-genotype relationships for the variable severity in clinical features between the severest ZS, NALD, and the mildest, IRD.We have isolated a human PEX1 cDNA (HsPEX1) by functional complementation of peroxisome deficiency of a mutant Chinese hamster ovary cell line, ZP107. PEX1 is the causative gene for PBDs of complementa … More tion group E (CG-E ; CG1 in USA/EU), the highest incidence PBD, and encodes the peroxin, Pex1p, a member of AAA-ATPase protein family. We earlier reported that temperature-sensitive peroxisome assembly is responsible for the mildness of the clinical features of IRD.It has been also reported that Pex1p and Pex6p interact with each other. In the present work, we investigated phenotype-genotype relationships of CG1 PBDs. Pex1p from IRD such as Pex1p with the frequently identified G843D was mostly degraded in vivo at 37℃, while it was detectable at a normal level in permissive temperature, 30℃. In contrast, Pex1p from ZS patients-derived PEX proteins, including each with a mutation at L664P or a deletion of amino acid residues at 634-690 were stably present at both temperatures. Pex1p-G843D interacted with Pex6p at 50% level of normal Pex1p, whilst Pex1p from ZS patients showing non-temperature-sensitive peroxisome biogenesis barely bound to Pex6p. Taken together, it is most likely that the stability of Pex1p reflects temperature-sensitive peroxisome assembly in IRD fibroblasts. Failure in Pex1p-Pex6p interaction gives rise to more severe abnormalities notable in ZS. Less

在这项对科学研究的赠款11680608的支持下，我们获得了以下发现：过氧化物体生物发生疾病（PBD），包括Zellweger综合征（ZS）（ZS）（ZS）（ZS）和Neonatal Adrenoleukodyromtrophy（Nald）和婴儿居民疾病（IRD），依从依次是诉讼，迫切需要依从性自动症。过氧化物体的故障，其中有12种基因型。 ZS患者表现出严重的临床和生化异常，而患有Nald和IRD的患者的严重程度和最轻度的特征分别显示出较少的临床和生化异常。然而，很少有人注意在分子级确定表型基因型关系，因为最严重的Zs，Nald和最轻度的IRD之间的临床特征的表型基因型关系通过功能完成了通过功能性完成突变的中国汉堡小羊肉细胞系的过氧化物缺乏，使人类PEX1 cDNA（HSPEX1）隔离了。 PEX1是pBD的真正基因，用于pbd的pBD，更多的E（CG-E； CG1；在美国/EU中的CG1），最高的发射率PBD，并编码了AAA-ATPase蛋白质家族的PEX1P，PEX1P，PEX1P。我们早些时候报道说，温度敏感的过氧组装组装负责IRD临床特征的温和性。还报道了PEX1P和PEX6P相互相互作用。在目前的工作中，我们研究了CG1 PBD的表型基因型关系。来自IRD的PEX1P，例如具有经常鉴定的G843D的PEX1P，大多在37°时在体内降解，而在宽敞温度下，可以在正常水平下检测到它，为30℃。相比之下，来自ZS患者衍生的PEX蛋白的PEX1P，包括在L664p处突变的每种PEX1P或在两个温度下在634-690处缺失在634-690时的氨基酸残留物。 PEX1P-G843D在正常PEX1P的50％水平上与PEX6P相互作用，而来自ZS患者的PEX1P表现出非温度敏感的过氧化物体生物发生几乎没有与PEX6P结合。综上所述，PEX1P的稳定性很可能反映了IRD成纤维细胞中温度敏感的过氧组件组件。 PEX1P-PEX6P相互作用的失败会导致ZS值得注意的异常。较少的