Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes.
Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes.
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DOI：
10.1038/s41598-018-35346-y
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发表时间：
2018-11-19
影响因子：
4.6
通讯作者：
Blair IA
中科院分区：
文献类型：
--
作者：
Guo L;Wang Q;Weng L;Hauser LA;Strawser CJ;Mesaros C;Lynch DR;Blair IA
Frataxin是一种高度保守的蛋白质，由Frataxin(FXN)基因编码。在细胞质中表达的全长210个氨基酸的蛋白质Frataxin(1-210；亚型A)迅速移位到线粒体，在线粒体上被线粒体加工肽酶转化为成熟的形式(81-210)。成熟的Frataxin(81-210)是一种非常重要的蛋白质，因为它促进了线粒体铁-硫簇蛋白复合体的组装，如乌头酸酶、脂酸盐合成酶和琥珀酸脱氢酶。Frataxin蛋白表达降低是造成Friedreich‘s共济失调这种罕见遗传性疾病的原因。长期以来，人们一直认为红细胞中存在Frataxin的线粒体形式，尽管自相矛盾的是，红细胞缺乏线粒体。我们发现红细胞Frataxin实际上是Frataxin的一种新的亚型(亚型E)，含有135个氨基酸和N-末端的乙酰化蛋氨酸残基。健康志愿者(n 10)全血红细胞中的E亚型(2 0.9 ± 6.4 ng/m L)是其他血细胞中成熟线粒体Frataxin(7.1 ± 1.0 ng/m L)的3倍。异构体E缺乏线粒体靶向序列，因此在培养细胞中表达时既分布于胞浆，也分布于细胞核。当线粒体外Frataxin异构体E在HEK 293细胞中表达时，它被转化为与线粒体中发现的成熟Frataxin相同的较短的异构体，这增加了它参与疾病病因的可能性。能够专门量化全血中的线粒体外和线粒体异构体Frataxin，这将使人们能够很容易地跟踪弗里德里希共济失调等疾病的自然历史，并监测治疗干预的效果。
Frataxin is a highly conserved protein encoded by the frataxin (FXN) gene. The full-length 210-amino acid form of protein frataxin (1–210; isoform A) expressed in the cytosol of cells rapidly translocates to the mitochondria, where it is converted to the mature form (81–210) by mitochondrial processing peptidase. Mature frataxin (81–210) is a critically important protein because it facilitates the assembly of mitochondrial iron-sulfur cluster protein complexes such as aconitase, lipoate synthase, and succinate dehydrogenases. Decreased expression of frataxin protein is responsible for the devastating rare genetic disease of Friedreich’s ataxia. The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 ± 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 ± 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich’s ataxia and monitor the efficacy of therapeutic interventions.
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影响因子：
3.8
作者：
Deutsch, Eric C.;Santani, Avni B.;Perlman, Susan L.;Farmer, Jennifer M.;Stolle, Catherine A.;Marusich, Michael F.;Lynch, David R.
通讯作者：
Lynch, David R.
影响因子：
13.6
作者：
Foley NM;Hughes GM;Huang Z;Clarke M;Jebb D;Whelan CV;Petit EJ;Touzalin F;Farcy O;Jones G;Ransome RD;Kacprzyk J;O'Connell MJ;Kerth G;Rebelo H;Rodrigues L;Puechmaille SJ;Teeling EC
通讯作者：
Teeling EC
影响因子：
16.6
作者：
Boniecki MT;Freibert SA;Mühlenhoff U;Lill R;Cygler M
通讯作者：
Cygler M
影响因子：
9.8
作者：
Arnesen T
通讯作者：
Arnesen T
影响因子：
4.2
作者：
Chiang, Shannon;Kalinowski, Danuta S.;Huang, Michael L-H
通讯作者：
Huang, Michael L-H