Molecular evolution of the LNX gene family.
Molecular evolution of the LNX gene family.
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DOI：
10.1186/1471-2148-11-235
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发表时间：
2011-08-09
影响因子：
3.4
通讯作者：
Young P
中科院分区：
文献类型：
--
作者：
Flynn M;Saha O;Young P
LNX（Numb蛋白X配体）蛋白通常含有一个氨基末端RING结构域，与两个或四个PDZ结构域相邻-这是LNX家族特有的结构域结构。LNX蛋白作为E3泛素连接酶发挥功能，其结构域组织表明其泛素连接酶活性可通过PDZ结构域介导的相互作用靶向特定底物或亚细胞位置。事实上，已经鉴定了LNX蛋白的许多相互作用伴侣，但大多数家族成员的体内功能仍然很不清楚。为了深入了解它们的功能，我们研究了LNX基因家族的系统发育起源和进化。我们发现，LNX 1/LNX 2样基因出现在早期后生动物谱系的基因复制和融合事件相结合的环结构域与四个PDZ结构域。这些PDZ结构域与多PDZ结构域蛋白-1（MUPP 1）的四个羧基末端结构域密切相关。LNX 1/LNX 2样基因的复制和随后的PDZ结构域的丢失似乎产生了编码LNX 3/LNX 4样蛋白的基因，只有两个PDZ结构域。该蛋白具有新的羧基末端序列，包括潜在的模块化LNX 3同源结构域。这两个祖先LNX基因存在于一些，但不是所有，无脊椎动物谱系。然而，它们在脊椎动物谱系中得以维持，进一步的复制事件在大多数哺乳动物中产生了五个LNX家族成员。此外，我们确定新的相互作用LNX 1和LNX 2与三个已知的MUPP 1配体使用酵母双杂交测定。这证明了LNX和MUPP 1 PDZ结构域之间结合特异性的保守性。LNX基因家族具有早期后生动物起源，其中LNX 1/LNX 2样蛋白可能通过PDZ结构域的丢失产生LNX 3/LNX 4样蛋白。在某些谱系中LNX直系同源物的缺乏表明LNX蛋白在无脊椎动物中不是必需的。相反，脊椎动物谱系中两个祖先LNX基因的维持表明获得了脊椎动物必需的特异性功能。LNX PDZ结构域与MUPP 1结构域在遗传学上相关，并具有共同的结合特异性，这一发现表明LNX和MUPP 1在细胞功能上可能具有相似性。
LNX (Ligand of Numb Protein-X) proteins typically contain an amino-terminal RING domain adjacent to either two or four PDZ domains - a domain architecture that is unique to the LNX family. LNX proteins function as E3 ubiquitin ligases and their domain organisation suggests that their ubiquitin ligase activity may be targeted to specific substrates or subcellular locations by PDZ domain-mediated interactions. Indeed, numerous interaction partners for LNX proteins have been identified, but the in vivo functions of most family members remain largely unclear. To gain insights into their function we examined the phylogenetic origins and evolution of the LNX gene family. We find that a LNX1/LNX2-like gene arose in an early metazoan lineage by gene duplication and fusion events that combined a RING domain with four PDZ domains. These PDZ domains are closely related to the four carboxy-terminal domains from multiple PDZ domain containing protein-1 (MUPP1). Duplication of the LNX1/LNX2-like gene and subsequent loss of PDZ domains appears to have generated a gene encoding a LNX3/LNX4-like protein, with just two PDZ domains. This protein has novel carboxy-terminal sequences that include a potential modular LNX3 homology domain. The two ancestral LNX genes are present in some, but not all, invertebrate lineages. They were, however, maintained in the vertebrate lineage, with further duplication events giving rise to five LNX family members in most mammals. In addition, we identify novel interactions of LNX1 and LNX2 with three known MUPP1 ligands using yeast two-hybrid asssays. This demonstrates conservation of binding specificity between LNX and MUPP1 PDZ domains. The LNX gene family has an early metazoan origin with a LNX1/LNX2-like protein likely giving rise to a LNX3/LNX4-like protein through the loss of PDZ domains. The absence of LNX orthologs in some lineages indicates that LNX proteins are not essential in invertebrates. In contrast, the maintenance of both ancestral LNX genes in the vertebrate lineage suggests the acquisition of essential vertebrate specific functions. The revelation that the LNX PDZ domains are phylogenetically related to domains in MUPP1, and have common binding specificities, suggests that LNX and MUPP1 may have similarities in their cellular functions.
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