Yahraus T, Braverman N, Dodt G, Kalish J E, Morrell J C, Moser H W, Valle D, Gould S J
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
EMBO J. 1996 Jun 17;15(12):2914-23.
In humans, defects in peroxisome assembly result in the peroxisome biogenesis disorders (PBDs), a group of genetically heterogeneous, lethal recessive diseases. We have identified the human gene PXAAA1 based upon its similarity to PpPAS5, a gene required for peroxisome assembly in the yeast Pichia pastoris. Expression of PXAAA1 restored peroxisomal protein import in fibroblasts from 16 unrelated members of complementation group 4 (CG4) of the PBD. Consistent with this observation, CG4 patients carry mutations in PXAAA1. The product of this gene, Pxaaa1p, belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein. Substitution of an arginine for the conserved lysine residue in the ATPase domain of Pxaaa1p abolished its biological activity, suggesting that Pxaaa1p is an ATPase. Furthermore, Pxaaa1p is required for stability of the predominantly cytoplasmic PTS1 receptor, Pxr1p. We conclude that Pxaaa1p plays a direct role in peroxisomal protein import and is required for PTS1 receptor activity.
在人类中，过氧化物酶体组装缺陷会导致过氧化物酶体生物发生障碍（PBDs），这是一组具有遗传异质性的致死性隐性疾病。我们基于人类基因PXAAA1与PpPAS5的相似性鉴定出了该基因，PpPAS5是酵母毕赤酵母中过氧化物酶体组装所需的基因。PXAAA1的表达恢复了来自PBD互补组4（CG4）的16名无亲缘关系成员的成纤维细胞中的过氧化物酶体蛋白导入。与这一观察结果一致，CG4患者在PXAAA1中携带突变。该基因的产物Pxaaa1p属于ATP酶的AAA家族，似乎是一种主要存在于细胞质中的蛋白质。用精氨酸替代Pxaaa1p的ATP酶结构域中保守的赖氨酸残基消除了其生物活性，表明Pxaaa1p是一种ATP酶。此外，Pxaaa1p是主要存在于细胞质中的PTS1受体Pxr1p稳定性所必需的。我们得出结论，Pxaaa1p在过氧化物酶体蛋白导入中起直接作用，并且是PTS1受体活性所必需的。
