RESUMO
Triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor expressed on the surface of microglia, macrophages, dendritic cells, and osteoclasts. The R47H TREM2 variant is a significant risk factor for late-onset Alzheimer's disease (AD), and the molecular basis of R47H TREM2 loss of function is an emerging area of TREM2 biology. Here, we report three high-resolution structures of the extracellular ligand-binding domains (ECDs) of R47H TREM2, apo-WT, and phosphatidylserine (PS)-bound WT TREM2 at 1.8, 2.2, and 2.2 Å, respectively. The structures reveal that Arg47 plays a critical role in maintaining the structural features of the complementarity-determining region 2 (CDR2) loop and the putative positive ligand-interacting surface (PLIS), stabilizing conformations capable of ligand interaction. This is exemplified in the PS-bound structure, in which the CDR2 loop and PLIS drive critical interactions with PS via surfaces that are disrupted in the variant. Together with in vitro and in vivo characterization, our structural findings elucidate the molecular mechanism underlying loss of ligand binding, putative oligomerization, and functional activity of R47H TREM2. They also help unravel how decreased in vitro and in vivo stability of TREM2 contribute to loss of function in disease.
Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Glicoproteínas de Membrana/química , Proteínas Mutantes/química , Receptores Imunológicos/química , Doença de Alzheimer/patologia , Cristalografia por Raios X , Células Dendríticas/química , Células Dendríticas/patologia , Variação Genética , Humanos , Ligantes , Macrófagos/química , Macrófagos/patologia , Glicoproteínas de Membrana/genética , Microglia/química , Microglia/patologia , Proteínas Mutantes/genética , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Osteoclastos/química , Osteoclastos/patologia , Conformação Proteica , Domínios Proteicos/genética , Receptores Imunológicos/genéticaRESUMO
We used mtDNA sequence variation to assess the origin, age, and spatial patterns of sequence divergence of triploid hybrid and diploid spontaneous parthenogens from southeastern United States populations of the freshwater snail Campeloma. There was strong support for multiple origins of both parthenogens using likelihood-ratio tests, and we argue that parthenogens are recently derived from sexuals. Atlantic coastal populations of C. limum or C. floridense were the maternal ancestors of Gulf Coast triploid hybrids in the Florida Panhandle. Sequence divergence within monophyletic groups of both parthenogens is similar to within-population divergence found in sympatric sexuals, and monophyletic clades of hybrid and spontaneous parthenogens are geographically widespread throughout the Atlantic and Gulf Coast rivers. These patterns are consistent with higher dispersal rates and recent range expansion of parthenogens, which should reduce the effects of mutation accumulation or parasitism. Range expansion may have occurred through interdrainage transfer during Pleistocene glacial periods.
