Abstract
Abstract The T cell Immunoglobulin and Mucin-like domain (TIM) proteins are a family of receptors that bind phosphatidylserine (PS) and regulate adaptive and innate immune cell functions. We find that two TIM-specific motifs: a G(W/L/I/F)(F/M)ND (GWFNDor) sequence and four conserved cysteine residues in the FG and CC’ segments of the TIM IgV domain form the distinctive PS-binding pocket identified in TIM-PS co-crystal structures. Because BALB/c and C57BL/6 mice have significant polymorphisms in TIM-3 and TIM-1, we determined the haplotypes of immunologically diverse and genetically divergent mice. Despite a high degree of variation in the IgV domain and in the mucin like stalk, the GWFNDor motif is unmodified in all known polymorphisms of TIM-1, -3, and 4. We identified two genomic alterations that cause divergent expression profiles of TIM-1 in commonly studied mouse strains. A major polymorphism in mouse TIM-1 deletes 23 amino acids of the mucin domain, and is caused by a retroviral insertion in the C57BL/6 genome that prevents expression of part of the mucin domain. Genomic and phylogenetic analyses show that a sytenic locus encoding generally 3 TIMs (1, 3, and 4) is conserved from bony fish to primates, and with emergence of the GWFND-4 motif in the most primitive TIM loci in bony fish, and the TIM family occupies a distinct PS-binding branch among the family of V-domain receptors that modulate immune activation via lipid, glycan, or protein binding.
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