Departments of Medicine, Pathology, Anthropology and Cellular and Molecular Medicine, Center for Academic Research and Training in Anthropogeny and Glycobiology Research and Training Center, University of California San Diego, San Diego, CA 92093, USA.
Department of Genetics, Princeton University, Princeton, NJ 08544, USA.
Mol Biol Evol. 2022 Aug 3;39(8). doi: 10.1093/molbev/msac151.
The myelomonocytic receptor CD33 (Siglec-3) inhibits innate immune reactivity by extracellular V-set domain recognition of sialic acid (Sia)-containing "self-associated molecular patterns" (SAMPs). We earlier showed that V-set domain-deficient CD33-variant allele, protective against late-onset Alzheimer's Disease (LOAD), is derived and specific to the hominin lineage. We now report multiple hominin-specific CD33 V-set domain mutations. Due to hominin-specific, fixed loss-of-function mutation in the CMAH gene, humans lack N-glycolylneuraminic acid (Neu5Gc), the preferred Sia-ligand of ancestral CD33. Mutational analysis and molecular dynamics (MD)-simulations indicate that fixed change in amino acid 21 of hominin V-set domain and conformational changes related to His45 corrected for Neu5Gc-loss by switching to N-acetylneuraminic acid (Neu5Ac)-recognition. We show that human-specific pathogens Neisseria gonorrhoeae and Group B Streptococcus selectively bind human CD33 (huCD33) as part of immune-evasive molecular mimicry of host SAMPs and that this binding is significantly impacted by amino acid 21 modification. In addition to LOAD-protective CD33 alleles, humans harbor derived, population-universal, cognition-protective variants at several other loci. Interestingly, 11 of 13 SNPs in these human genes (including CD33) are not shared by genomes of archaic hominins: Neanderthals and Denisovans. We present a plausible evolutionary scenario to compile, correlate, and comprehend existing knowledge about huCD33-evolution and suggest that grandmothering emerged in humans.
髓系细胞表面受体 CD33（Siglec-3）通过识别含有唾液酸（Sia）的“自身相关分子模式”（SAMPs）的细胞外 V -set 结构域来抑制固有免疫反应。我们之前的研究表明，对迟发性阿尔茨海默病（LOAD）具有保护作用的 CD33 变体等位基因缺乏 V-set 结构域，这种等位基因是人类特有的。我们现在报告了多个人类特异性的 CD33 V-set 结构域突变。由于人类 CMAH 基因的特异性、固定的失活突变，人类缺乏 N-羟乙酰神经氨酸（Neu5Gc），这是祖先 CD33 的首选 Sia 配体。突变分析和分子动力学（MD）模拟表明，人类 V-set 结构域第 21 位氨基酸的固定变化以及与 His45 相关的构象变化通过切换到 N-乙酰神经氨酸（Neu5Ac）识别来纠正 Neu5Gc 的丢失。我们表明，人类特有的病原体淋病奈瑟菌和 B 族链球菌选择性地结合人 CD33（huCD33），作为宿主 SAMPs 免疫逃避分子模拟的一部分，而这种结合受到第 21 位氨基酸修饰的显著影响。除了具有 LOAD 保护作用的 CD33 等位基因外，人类还在其他几个基因座上携带衍生的、具有群体普遍性的认知保护变体。有趣的是，这些人类基因（包括 CD33）中的 13 个 SNP 中有 11 个不在古人类（尼安德特人和丹尼索瓦人）的基因组中共享。我们提出了一个合理的进化情景，以整理、关联和理解关于 huCD33 进化的现有知识，并提出祖母基因在人类中出现。
