Burroughs A Maxwell, Nicastro Gianlucca G, Aravind L
Division of Intramural Research, National Library of Medicine, National Institutes of Health, Bethesda, United States.
Elife. 2025 Sep 9;14:RP108061. doi: 10.7554/eLife.108061.
Wnt proteins are critical signaling molecules in developmental processes across animals. Despite intense study, their evolutionary roots have remained enigmatic. Using sensitive sequence analysis and structure modeling, we establish that the Wnts are part of a vast assemblage of domains, the Lipocone superfamily, defined here for the first time. It includes previously studied enzymatic domains like the phosphatidylserine synthases (PTDSS1/2) and the TelC toxin domain from , the enigmatic VanZ proteins, the animal Serum Amyloid A (SAA), and a further host of uncharacterized proteins in a total of 30 families. Although the metazoan Wnts are catalytically inactive, we present evidence for a conserved active site across this superfamily, versions of which are consistently predicted to operate on head groups of either phospholipids or polyisoprenoid lipids, catalyzing transesterification and phosphate-containing head group cleavage reactions. We argue that this superfamily originated as membrane proteins, with one branch (including Wnt and SAA) evolving into diffusible versions. By comprehensively analyzing contextual information networks derived from comparative genomics, we establish that they act in varied functional contexts, including regulation of membrane lipid composition, extracellular polysaccharide biosynthesis, and biogenesis of bacterial outer-membrane components, like lipopolysaccharides. On multiple occasions, members of this superfamily, including the bacterial progenitors of Wnt and SAA, have been recruited as effectors in biological conflicts spanning inter-organismal interactions and anti-viral immunity in both prokaryotes and eukaryotes. These findings establish a unifying theme in lipid biochemistry, explain the origins of Wnt signaling, and provide new leads regarding immunity across the tree of life.
Wnt蛋白是动物发育过程中的关键信号分子。尽管经过了深入研究，但其进化根源仍然扑朔迷离。通过灵敏的序列分析和结构建模，我们确定Wnt蛋白是一个庞大的结构域组合——Lipocone超家族的一部分，这是首次在此定义该超家族。它包括先前研究过的酶结构域，如磷脂酰丝氨酸合酶（PTDSS1/2）和来自[具体来源未明确]的TelC毒素结构域、神秘的VanZ蛋白、动物血清淀粉样蛋白A（SAA），以及总共30个家族中的大量未表征蛋白。尽管后生动物的Wnt蛋白没有催化活性，但我们提供了证据表明在这个超家族中存在一个保守的活性位点，其不同版本一直被预测作用于磷脂或聚异戊二烯脂质的头部基团，催化酯交换反应和含磷酸头部基团切割反应。我们认为这个超家族起源于膜蛋白，其中一个分支（包括Wnt和SAA）进化成了可扩散的形式。通过全面分析来自比较基因组学的上下文信息网络，我们确定它们在多种功能环境中发挥作用，包括调节膜脂组成、细胞外多糖生物合成以及细菌外膜成分（如脂多糖）的生物合成。在多个情况下，这个超家族的成员，包括Wnt和SAA的细菌祖先，在跨越生物体间相互作用和原核生物与真核生物抗病毒免疫等生物冲突中被招募为效应器。这些发现确立了脂质生物化学中的一个统一主题，解释了Wnt信号传导的起源，并为整个生命树中的免疫提供了新线索。
