Table11_Origin and Evolution of the Multifaceted Adherens Junction Component Plekha7.xlsx

Plekha7 is a key adherens junction component involved in numerous functions in mammalian cells. Plekha7 is the most studied member of the PLEKHA protein family, which includes eight members with diverse functions. However, the evolutionary history of Plekha7 remains unexplored. Here, we outline the phylogeny and identify the origins of this gene and its paralogs. We show that Plekha7, together with Plekha4, Plekha5, and Plekha6, belong to a subfamily that we name PLEKHA4/5/6/7. This subfamily is distinct from the other Plekha proteins, which form two additional separate subfamilies, namely PLEKHA1/2 and PLEKHA3/8. Sequence, phylogenetic, exon-intron organization, and syntenic analyses reveal that the PLEKHA4/5/6/7 subfamily is represented by a single gene in invertebrates, which remained single in the last common ancestor of all chordates and underwent gene duplications distinctly in jawless and jawed vertebrates. In the latter species, a first round of gene duplications gave rise to the Plekha4/7 and Plekha5/6 pairs and a second round to the four extant members of the subfamily. These observations are consistent with the 1R/2R hypothesis of vertebrate genome evolution. Plekha7 and Plekha5 also exist in two copies in ray-finned fishes, due to the Teleostei-specific whole genome duplication. Similarities between the vertebrate Plekha4/5/6/7 members and non-chordate sequences are restricted to their N-terminal PH domains, whereas similarities across the remaining protein molecule are only sporadically found among few invertebrate species and are limited to the coiled-coil and extreme C-terminal ends. The vertebrate Plekha4/5/6/7 proteins contain extensive intrinsically disordered domains, which are topologically and structurally conserved in all chordates, but not in non-chordate invertebrates. In summary, our study sheds light on the origins and evolution of Plekha7 and the PLEKHA4/5/6/7 subfamily and unveils new critical information suitable for future functional studies of this still understudied group of proteins.

Plekha7蛋白作为哺乳动物细胞中众多功能的关键粘附连接组分，是该家族中最受研究的成员。PLEKHA蛋白家族共包含八个成员，各司其职，而Plekha7的进化历程尚未被揭示。本研究旨在梳理其系统发育树，并探究该基因及其同源基因的起源。我们发现Plekha7与Plekha4、Plekha5及Plekha6共同构成一个子家族，命名为PLEKHA4/5/6/7。该子家族与其它PLEKHA蛋白家族成员构成两个独立的子家族，即PLEKHA1/2和PLEKHA3/8。序列分析、系统发育分析、外显子-内含子组织结构和同源分析表明，PLEKHA4/5/6/7子家族在无脊椎动物中仅由一个基因代表，该基因在所有脊索动物最近的共同祖先中保持单一状态，并在无颌和有颌脊椎动物中经历了显著的基因复制。在后一类物种中，第一次基因复制产生了Plekha4/7和Plekha5/6两个基因对，第二次复制则形成了该子家族现存的四个成员。这些发现与脊椎动物基因组进化的1R/2R假说相吻合。在辐鳍鱼类中，由于辐鳍鱼类特有的全基因组复制，Plekha7和Plekha5也存在两个拷贝。脊椎动物的PLEKHA4/5/6/7成员与非脊索动物序列的相似性局限于其N端PH结构域，而蛋白质分子其余部分的相似性仅在少数无脊椎动物物种中零星发现，且限于螺旋结构域和极端的C端端。脊椎动物的PLEKHA4/5/6/7蛋白含有广泛的内在无序结构域，这些结构域在所有脊索动物中拓扑和结构上保守，但在非脊索动物无脊椎动物中则不然。总之，本研究揭示了Plekha7及其PLEKHA4/5/6/7子家族的起源和进化，并为未来对该类蛋白质仍处于研究阶段的蛋白群的功能研究提供了新的关键信息。