Glaser Elzbieta, Alikhani Nyosha
Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden.
Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1076-80. doi: 10.1016/j.bbabio.2009.12.016. Epub 2009 Dec 28.
The novel peptidasome, called presequence protease, PreP, was originally identified and characterized in Arabidopsis thaliana as a mitochondrial matrix and chloroplast stroma localized metalloprotease. PreP has a function as the organellar peptide clearing protease and is responsible for degrading free targeting peptides and also other unstructured peptides up to 65 amino acid residues that might be toxic to organellar functions. PreP contains an inverted Zn-binding motif and belongs to the pitrilysin protease family. The crystal structure of AtPreP refined at 2.1 A demonstrated a unique totally enclosed large cavity of 10000 A3 that opens and closes in response to peptide binding, revealing a novel catalytic mechanism for proteolysis. Homologues of PreP have been found in yeast and human mitochondria. Interestingly, the human PreP, hPreP, is the protease that is responsible for clearing the human brain mitochondria from the toxic amyloid-beta peptide (Abeta) associated with Alzheimer's disease (AD). Accumulation of Abeta has been shown in the brain mitochondria from AD patients and mutant transgenic mice overexpressing Abeta. Here, we present a review of our present knowledge on structural and functional characteristics of PreP and discuss its mitochondrial Abeta-degrading activity in the human brain mitochondria in relation to AD.
这种名为前序列蛋白酶（PreP）的新型肽体最初是在拟南芥中被鉴定和表征的，它是一种定位于线粒体基质和叶绿体基质的金属蛋白酶。PreP作为细胞器肽清除蛋白酶，负责降解游离的靶向肽以及其他长度达65个氨基酸残基的无结构肽，这些肽可能对细胞器功能有毒害作用。PreP含有一个反向锌结合基序，属于pitrilysin蛋白酶家族。AtPreP在2.1埃分辨率下的晶体结构显示出一个独特的、完全封闭的10000埃³大腔，该腔会根据肽结合情况打开和关闭，揭示了一种新的蛋白水解催化机制。在酵母和人类线粒体中也发现了PreP的同源物。有趣的是，人类PreP（hPreP）是负责清除人类脑线粒体中与阿尔茨海默病（AD）相关的有毒淀粉样β肽（Aβ）的蛋白酶。在AD患者和过表达Aβ的突变转基因小鼠的脑线粒体中已显示出Aβ积累。在此，我们综述了目前关于PreP结构和功能特征的知识，并讨论了其在人类脑线粒体中与AD相关的线粒体Aβ降解活性。
