Khwaja Mirium, Ma Qinhong, Saier Milton H
Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093-0116, USA.
Res Microbiol. 2005 Mar;156(2):270-7. doi: 10.1016/j.resmic.2004.07.010. Epub 2004 Nov 11.
The ATP binding cassette (ABC) superfamily consists of dozens of families of transport systems, each of which catalyzes uptake or efflux of a specific type of molecule using ATP hydrolysis to energize transport. While all of the ATP hydrolyzing subunits in the superfamily are homologous, a monophyletic origin of the integral membrane constituents is not established. We have identified a subset of these transmembrane proteins that have a basal unit of four transmembrane alpha-helical segments (TMSs) with a large extracytoplasmic domain between TMSs 1 and 2. These homologues were found to exhibit 4, 8 or 10 putative TMSs per polypeptide chain. The two larger topological types exhibit a 4 TMS repeat element resulting from an internal gene duplication event, and the 10 TMS proteins display an extra two putative TMSs between the two repeat units. Rare intragenic deletions in these homologues gave rise to truncated proteins lacking the extracytoplasmic domain, and some phylogenetic clusters of the 4 TMS membrane proteins (but not the 8 or 10 TMS proteins) are fused N-terminal (never C-terminal) to ATP hydrolyzing domains. Bioinformatic analyses lead to the suggestion that in the larger homologues, the second repeat units are more important for function than the first repeat units. Operon analyses suggest that the 4 TMS proteins form heterodimeric complexes while the 8 and 10 TMS proteins incorporate the equivalent of these complexes into single integral membrane polypeptide chains. Different gene compositions of the operons encoding the 4 versus 8 and 10 TMS homologues suggest that these two structural types of transporters act on different types of substrates and serve dissimilar functions. Significant sequence similarity between the integral membrane constituents of the ABC efflux pumps analyzed here and those of other ABC transporters could not be detected. These studies define the evolutionary pathway taken for the appearance of a subset of ABC transmembrane transport proteins and provide clues regarding their mechanistic and functional characteristics.
ATP结合盒（ABC）超家族由数十个转运系统家族组成，每个家族利用ATP水解提供能量来催化特定类型分子的摄取或外排。虽然超家族中所有的ATP水解亚基都是同源的，但完整膜成分的单系起源尚未确定。我们已经鉴定出这些跨膜蛋白的一个子集，它们具有由四个跨膜α螺旋段（TMS）组成的基本单元，在TMS 1和TMS 2之间有一个大的胞外结构域。发现这些同源物每条多肽链有4、8或10个推定的TMS。两种较大的拓扑类型表现出由内部基因复制事件产生的4个TMS重复元件，10个TMS蛋白在两个重复单元之间显示出另外两个推定的TMS。这些同源物中罕见的基因内缺失产生了缺乏胞外结构域的截短蛋白，并且4个TMS膜蛋白（但不是8个或10个TMS蛋白）的一些系统发育簇在N端（从不C端）与ATP水解结构域融合。生物信息学分析表明，在较大的同源物中，第二个重复单元对功能比第一个重复单元更重要。操纵子分析表明，4个TMS蛋白形成异二聚体复合物，而8个和10个TMS蛋白将这些复合物的等效物整合到单个完整膜多肽链中。编码4个与8个和10个TMS同源物的操纵子的不同基因组成表明，这两种结构类型的转运蛋白作用于不同类型的底物并发挥不同的功能。在此分析的ABC外排泵的完整膜成分与其他ABC转运蛋白之间未检测到显著的序列相似性。这些研究确定了ABC跨膜转运蛋白一个子集出现所采用的进化途径，并提供了有关其机制和功能特征的线索。
