Department of Immunology, Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
Oncode Institute, Utrecht, The Netherlands.
PLoS One. 2021 Mar 29;16(3):e0244770. doi: 10.1371/journal.pone.0244770. eCollection 2021.
The inhibitory signaling of CD200 receptor 1 (CD200R) has been attributed to its NPxY signaling motif. However, NPxY-motifs are present in multiple protein families and are mostly known to mediate protein trafficking between subcellular locations rather than signaling. Therefore, we investigated whether additional motifs specify the inhibitory function of CD200R. We performed phylogenetic analysis of the intracellular domain of CD200R in mammals, birds, bony fish, amphibians and reptiles. Indeed, the tyrosine of the NPxY-motif is fully conserved across species, in line with its central role in CD200R signaling. In contrast, P295 of the NPxY-motif is not conserved. Instead, a conserved stretch of negatively charged amino acids, EEDE279, and two conserved residues P285 and K292 in the flanking region prior to the NPxY-motif are required for CD200R mediated inhibition of p-Erk, p-Akt308, p-Akt473, p-rpS6 and LPS-induced IL-8 secretion. Altogether, we show that instead of the more common NPxY-motif, CD200R signaling can be assigned to a unique signaling motif in mammals defined by: EEDExxPYxxYxxKxNxxY.
CD200 受体 1（CD200R）的抑制信号归因于其 NPxY 信号基序。然而，NPxY 基序存在于多个蛋白家族中，主要已知的作用是介导蛋白在亚细胞位置之间的运输，而不是信号传递。因此，我们研究了是否有其他基序可以指定 CD200R 的抑制功能。我们对哺乳动物、鸟类、硬骨鱼、两栖动物和爬行动物的 CD200R 胞内域进行了系统发育分析。实际上，NPxY 基序中的酪氨酸在跨物种中是完全保守的，与其在 CD200R 信号中的核心作用一致。相比之下，NPxY 基序中的 P295 并不保守。相反，在 NPxY 基序之前的侧翼区域中有一段保守的带负电荷的氨基酸 EEDE279，以及两个保守残基 P285 和 K292，对于 CD200R 介导的 p-Erk、p-Akt308、p-Akt473、p-rpS6 和 LPS 诱导的 IL-8 分泌的抑制作用是必需的。总之，我们表明，CD200R 的信号传递不是更常见的 NPxY 基序，而是可以被指定为哺乳动物中独特的信号基序，该基序由：EEDExxPYxxYxxKxNxxY 定义。
