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

基本信息

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

项目摘要

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

在这项科学研究11680608的支持下，我们获得了以下发现：过氧化物酶体生物发生障碍（PBDS）响亮的Zellweger综合征（ZS）和新生儿脂肪营养不良（NALD）和婴儿抗蛋白酶疾病（IRD）的衰减（IRD）疾病中的疾病，由Peroxise sass造成的疾病中的缺陷很好过氧化物组的故障表现出严重程度和生物化学性，而纳尔德（Nald）和ird的严重性较小，最温和的特征却很少。最温和的IRD。我们通过功能互补的互补性互补，是在美国/EU中的CG1，CG1，最高的INCIDEENCE PBD，并编码过氧蛋白PEX1P，PEX1P1P ，我们早些时候报道了温度敏感的过氧化物酶体组装负责IRD的E临床特征的温和性。还报道了PEX1P和PEX6P在目前的工作中相互作用。在37°C下进行体内ed，而在宽敞温度下是在正常lo中的缺失，30°C。相反，ZS患者衍生的蛋白质的PEX1P，包括在L664p或氨基酸残基的突变，包括每个蛋白质的pex1p。 634-690个PEX1P-G843D与PEX6P相互作用，在50％的PEX1P水平上，而PEX1P的ZS患者显示出非温和的生物形成