TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease.
TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease.
复制标题
TM6SF2和MAC30，固醇代谢和常见代谢疾病的新酶同源物。
DOI：
10.3389/fgene.2014.00439
复制
发表时间：
2014
影响因子：
3.7
通讯作者：
Ponting CP
中科院分区：
文献类型：
--
作者：
Sanchez-Pulido L;Ponting CP
TM 6SF 2基因中Glu 167 Lys编码变体的携带者最近被鉴定为更易患非酒精性脂肪肝（NAFLD），但表现出较低的循环脂质水平，因此可以预防心血管疾病。尽管这些观察结果的生理重要性，TM 6SF 2的分子功能仍然未知，并没有序列相似性的功能特征的蛋白质已被确定。为了追溯其进化历史和确定功能结构域，我们开始了一个计算的蛋白质序列分析TM 6SF 2。我们鉴定了一个新的结构域，EXPERA结构域，它在TM 6SF，MAC 30/TMEM 97和EBP（D8，D 7甾醇异构酶）蛋白家族中是保守的。EBP突变是点状软骨发育不良2型X连锁显性（CDPX 2）的原因，也称为Conradi-Hünermann-Happle综合征，一种胆固醇生物合成缺陷性疾病。我们的进化保守EXPERA域的家庭和以前提出的EBP酶的催化机制之间的分析表明，TM 6SF和MAC 30/TMEM 97家庭都很可能拥有，作为EBP家庭，甾醇异构酶的催化活性。这种对TM 6SF和MAC 30/TMEM 97酶功能的意外预测是重要的，因为它现在允许详细的实验来研究这些关键蛋白质在从心血管疾病到癌症的各种人类病理学中的功能。
Carriers of the Glu167Lys coding variant in the TM6SF2 gene have recently been identified as being more susceptible to non-alcoholic fatty liver disease (NAFLD), yet exhibit lower levels of circulating lipids and hence are protected against cardiovascular disease. Despite the physiological importance of these observations, the molecular function of TM6SF2 remains unknown, and no sequence similarity with functionally characterized proteins has been identified. In order to trace its evolutionary history and to identify functional domains, we embarked on a computational protein sequence analysis of TM6SF2. We identified a new domain, the EXPERA domain, which is conserved among TM6SF, MAC30/TMEM97 and EBP (D8, D7 sterol isomerase) protein families. EBP mutations are the cause of chondrodysplasia punctata 2 X-linked dominant (CDPX2), also known as Conradi-Hünermann-Happle syndrome, a defective cholesterol biosynthesis disorder. Our analysis of evolutionary conservation among EXPERA domain-containing families and the previously suggested catalytic mechanism for the EBP enzyme, indicate that TM6SF and MAC30/TMEM97 families are both highly likely to possess, as for the EBP family, catalytic activity as sterol isomerases. This unexpected prediction of enzymatic functions for TM6SF and MAC30/TMEM97 is important because it now permits detailed experiments to investigate the function of these key proteins in various human pathologies, from cardiovascular disease to cancer.