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Paired opposing leukocyte receptors recognizing rapidly evolving ligands are subject to homogenization of their ligand binding domains - PubMed

Paired opposing leukocyte receptors recognizing rapidly evolving ligands are subject to homogenization of their ligand binding domains

Sigbjørn Fossum et al. Immunogenetics. 2011 Dec.

Abstract

Some leukocyte receptors come in groups of two or more where the partners share ligand(s) but transmit opposite signals. Some of the ligands, such as MHC class I, are fast evolving, raising the problem of how paired opposing receptors manage to change in step with respect to ligand binding properties and at the same time conserve opposite signaling functions. An example is the KLRC (NKG2) family, where opposing variants have been conserved in both rodents and primates. Phylogenetic analyses of the KLRC receptors within and between the two orders show that the opposing partners have been subject to post-speciation gene homogenization restricted mainly to the parts of the genes that encode the ligand binding domains. Concerted evolution similarly restricted is demonstrated also for the KLRI, KLRB (NKR-P1), KLRA (Ly49), and PIR receptor families. We propose the term merohomogenization for this phenomenon and discuss its significance for the evolution of immune receptors.

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Figures

Fig. 1
Fig. 1

Amino acid sequences of rat (r) and mouse (m) KLRC receptors. Dashes indicate identity with top sequence (rat NKG2E); points indicate gaps. Numbers on top of alignment show the start site of corresponding exons. Cytoplasmic ITIM are boxed; additional ITIM-like motifs are boxed with broken lines. Putative TM regions are underlined. Below the alignment are indicated conserved secondary motifs in the CLSF lectin-like domains (e.g., α1—α-helix 1, β1—β-strand 1, L1—loop 1)

Fig. 2
Fig. 2

Exonwise comparisons of substitution sites in KLRC genes. a Mouse (mm) versus rat (rt), b human versus chimpanzee (pt), and c human (hs) versus rhesus monkey (rm). Nucleotide sequences for each exon were aligned and sites were removed if one of the following conditions was fulfilled: (1) all bases were identical, (2) only one of the genes differed from the others, (3) one or more of the genes exhibited gaps. The bases were replaced by symbols, where filled circles indicate the identity with the top sequence and the other symbols (open circles, red squares, blue inverted pyramids) the non-identical bases. Above the sequences are shown exon numbers, and in a also the numbers of compared bases. For example, 115 bases were compared for exon 6. At 92 sites, all six were identical and at ten sites only one of the six deviated from the others. These 102 sites were omitted, leaving the 13 sites shown. a The truncated exon 3 of mmNnkg2e shown in Fig. 1 (reported in Vance et al. 1998) may represent a splice variant; in the mouse genome sequence mmNkg2e was found to contain a sequence identical to exon 3 of mmNkg2c, as shown here. The alignment for exon 5 has been extended ~100 nt into intron 5 (@|in5) to demonstrate the changing affiliation of mmNkg2e (see “Results”). b The sequence referred to as ptC is based on the ptNKG2CI 01 allele (Khakoo et al. 2000). ptNKG2CII has, for clarity, been omitted. Single asterisk, hsNKG2F and ptNKG2F lack exons 5 and 6. b, c Two asterisks, as first described for hsNKG2E (Adamkiewicz et al. 1994) this gene as well as ptNKG2E and rmNKG2FE have insertion–deletion affecting the last ~20 nt of exon 6, resulting in sequence alteration of the conserved β5-strand, including the loss of the cysteine involved in disulphide bonding to the α1-helix. These sites are not shown

Fig. 3
Fig. 3

Exonwise comparisons of rodent and primate KLRC nucleotide sequences. a Mouse (m) versus rat (r), b human (h) versus chimpanzee (p), c human versus rhesus monkey (m), d human (h) versus rat (r). A, C, E, and F refer to NKG2 family member names. Presumed or proven inhibitory receptors (with ITIMs) shown in red and with minus sign; receptors without ITIMs are in blue and with plus sign. Background colors indicate species. Exon 1 at the bottom and exon 6 at the top. The lengths of the vertical lines are proportional to nucleotide differences

Fig. 4
Fig. 4

Exonwise comparisons between mouse and rat KLRI, KLRB and PIR receptors. Mouse sequences indicated with m and red background; rat sequences indicated with r and blue background (coding exons only). For KLRI (a) and KLRB (b), the comparisons were made at the nucleotide level between each of the six coding exons. Exon 1 at the bottom and exon 6 at the top. For PIR (c), the comparisons were made at the amino acid level between the STPs (left) and the six Ig loops of the LBDs (right). Red and blue letters and +/− signs as in Fig. 3. a 1—KLRI1 is inhibitory, 2—KLRI2 is activating. b A, B, C, D, E, and F indicate NKR-P1 family member. c A1 through A6 denote the corresponding, presumed activating, PIR-A receptors; B—the ITIM-bearing PIR-B receptor

Fig. 5
Fig. 5

Exonwise comparisons between selected rat and mouse KLRA (Ly49) receptors. Mouse sequences m and red background; rat sequences—r and blue background. The comparisons were made at the amino acid level, with sequences grouped into STPs (cytoplasmic and transmembrane domains encoded by exons 2 and 3), the stalk (encoded by exon 4), and the lectin-like domain (encoded by exons 5–7). Red—ITIM-bearing receptors, blue—non-ITIM-bearing and transmembrane arginine, black—receptors with both features (“bifunctional”). Branches with roman numbers I–III indicate rat receptors encoded by chromosomal segments (blocks) I–III (see text). Arabic numbers indicate bootstrapping values in percent (1,000 iterations). It should be noted that the STP of the activating variants form three separate branches and persistently do so with variation of parameters when tested both at the amino acid and at the nucleotide level and when the exons encoding the cytoplasmic tail and the TM are analyzed separately or together

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