Identification of novel PEX gene and functional analysis of Pexlp in peroxisome biogenesis

新型PEX基因的鉴定及Pexlp在过氧化物酶体生物合成中的功能分析

• 批准号: 13680694
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13680694/
• 关键词: peroxisome; peroxisome biogenesis disorders; CHO cell mutants; peroxins; pathogenic genes; membrane proteins; AAA ATPase family; protein-protein interaction; AAAファミリータンパク質; 患者解析; タンパク質相互作用; 機能相補クローニング; 温度感受性

1) We investigated phenotype-genotype relationships of CGI peroxisome biogenesis disorders (PBDs). Pex1p from IRD such as Pex1p with the most frequently identified mutation at G843D was largely degraded in vivo at 37℃, whereas a normal level of Pexlp was detectable at the permissive temperature. In contrast, PEX1 proteins derived from ZS patients, including proteins with a mutation at L664P or the deletion of residues 634-690, were stably present at both temperatures. Pex1p-G843D interacted with Pex6p at appox. 50% of the level of normal Pex1p, whereas Pex1p from ZS patients mostly showing non-temperature-sensitive peroxisome biogenesis hardly bound to Pex6p. Taking these results together, we consider it most likely that the stability of Pexlp reflects temperature-sensitive peroxisome assembly in IRD fibroblasts. Failure in Pex1p-Pex6p interaction gives rise to more severe abnormalities, such as those manifested by patients with ZS.2) We showed that PEX6, the CG4 pathogenic gene, restored peroxisome assembly in CG6 PBD fibroblasts. This patient was compound heterozygous for PEX6 alleles. Accordingly, human PBDs are classified into 12 CGs by merging CG6 with CG4.3) We recently isolated human PEX26 encoding a novel, 34-kDa type II peroxisomal membrane protein, using a CHO cell mutant ZP167. PEX26 expression restored peroxisomal protein import in only the CG8 PBD patient's fibroblasts. This patient possessed a homozygous, inactivating pathogenic point mutation, R98W. Accordingly, we can state that all of pathogenic genes responsible for 12 CGs PBDs have been cloned. Moreover, Pex6p and Pex1p of the AAA ATPase family were co-immunoprecipitated with Pex26p. Together with several lines of morphological evidence, we concluded that Pex26p recruits Pex6p-Pex1p complexes to peroxisomes.

1）我们研究了CGI过氧化物酶体生物发生障碍的表型基因型（PBD）。 ，在正常的PEX1P的两个温度下，具有L664p突变的倾斜蛋白质稳定存在。 PECLP反映了IRD中温度敏感的过氧化物酶体在PEX1P-PEX6P相互作用。 PEX6等位基因的杂合患者具有纯合的致病点突变，R98W已被pex6p和PEX26P pex26p conpectecom pex26p pex16p peexs pex16p pex16p， 。

项目成果

Matsumoto,N.: "The novel pathogenic perxim Pex26p recruits the Pex1p-Pex6p AAA-ATPase complexes to peroxisomes"Nat. Cell. Biol.. 5. 454-460 (2003)

Matsumoto,N.：“新型致病性 Perxim Pex26p 将 Pex1p-Pex6p AAA-ATP 酶复合物招募到过氧化物酶体”Nat。

Matsumoto, N.: "Mutations in novel peroxin gene PEX26 that cause peroxisome biogenesis disorders of complementation group 8 provide a genotype-phenotype correlation"Am.J.Hum.Genet.. (in press). (2003)

Matsumoto, N.：“新型过氧化物酶基因 PEX26 中的突变导致互补组 8 的过氧化物酶体生物发生障碍，提供了基因型-表型相关性”Am.J.Hum.Genet..（出版中）。

Matsumoto, N.: "The novel pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA-ATPase complexes to peroxisomes"Nat.Cell Biol.. (in press). (2003)

Matsumoto, N.：“新型致病性过氧化物蛋白 Pex26p 将 Pex1p-Pex6p AAA-ATP 酶复合物募集到过氧化物酶体”Nat.Cell Biol..（出版中）。

Matsumoto, N.: "The peroxin Pex6p gene is impaired in peroxisomal biogenesis disorders of complementation group 6"J Hum Genet.. 46. 273-277 (2001)

Matsumoto, N.：“过氧化物酶体 Pex6p 基因在互补组 6 的过氧化物酶体生物发生障碍中受损”J Hum Genet.. 46. 273-277 (2001)

Matsumoto, N.: "The novel pathogenic peroxin Pex26p recruits the Pex1p-Pex6p AAA-ATPase complexes to peroxisomes"Nat.Cell Biol. 5. 454-460 (2003)

Matsumoto, N.：“新型致病性过氧化物蛋白 Pex26p 将 Pex1p-Pex6p AAA-ATP 酶复合物招募到过氧化物酶体”Nat.Cell Biol。