| Abstrakt: |
Genes of the major histocompatibility complex (MHC; also called HLA in human) are polymorphic elements in the genomes of sharks to humans. Class-I and class-II MHC loci appear responsible for much of the genetic linkage to myriad disease states via the capacity to bind short (~8-15 a.a.) peptides of a given pathogen's proteome, or in some cases, the altered proteomes of cancerous cells, and even (in autoimmunity) certain nominal ‘self’ peptides (Janeway, 2004).1Unfortunately, little is known about how the canonical structure of the MHC-I/-II peptide-presenting gene evolved, particularly since beyond ~500 Mya (sharks) no paralogs exist.2,3We previously reported that HLA-A isotype alleles with the α1-helix, R65 motif, are wide-spread in phylogeny, but that the α 2-helix, H151R motif, has apparently segregated out of most species. Surprisingly, an uncharacterizedorfinT. syrichta(Loc-103275158) encoded R151, but within a truncated A-23 like gene containing 5′- and 3′- footprints of the transposon (TE),tigger-1; the extant tarsier A-23 allele is totally missing exon-3 and part-of exon-4; together, suggesting TE-mediated inactivation of an intact/ancestral A-23 allele (Murray, 2015a).4The uniqueLoc-103275158 orfencodes a putative 15-exon transcript with no apparent paralogs throughout phylogeny. However, an HLA-A11 like gene inM. leucophaeuswith a shortened C-terminal domain, and an HLA-A likeorfinC. atyswith two linked α1/α2/α3 domains, both contain a second transmembrane segment, which is conserved inLoc-103275158. Thus, we could model the putative protein with its Nef-like tail domain docked to its MHC-I like α3 domain (i.e., on the same side of a membrane). This modeled tertiary structure is strikingly similar to the solved structure of the Nef:MHC-I CD:AP1mu transporter (Jia, 2012).5Nef:AP1mu binds the CD of MHC-I in trafficking MHC-I away from the trans-golgi and into the endocytic pathway in HIV-1 infected cells. The CD loop of theLoc-103275158provisional protein conserved the nominal MHC-I CD tyrosine phosphorylation site, and it has an N-terminal SH3 domain that we docked in one conformation to its internal Nef-like domain. Here, we suggest that phosphorylation of the protein's CD-loop signals an exchange between the internal Nef-like domain and a lentiviral-Nef for binding the N-terminal SH3 domain - freeing the Nef-like domain to bind MHC-I CD. Since the 5′-tiggersequence encodes part of the pseudo α1/α2 MHC-I domain, and the 3′-tiggerpart of the Nef-like domain, we speculate that transposition proceeded phylogenetically disparate horizontal transfers, involving adjacent 5′- and 3′- parasitic footprints, which we also found in theLoc-103275158 orf. [ABSTRACT FROM AUTHOR] |
