TE-domestication and horizontal transfer in a putative Nef-AP1mu mimic of HLA-A cytoplasmic domain re-trafficking

Abstract

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).1 Unfortunately, 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, 3 We previously reported that HLA-A isotype alleles with the a1-helix, R65 motif, are wide-spread in phylogeny, but that the a 2-helix, H151R motif, has apparently segregated out of most species. Surprisingly, an uncharacterized orf in T. syrichta (Loc-103275158) encoded R151, but within a truncated A-23 like gene containing 5 0 -and 3 0 -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). 4 The unique Loc-103275158 orf encodes a putative 15-exon transcript with no apparent paralogs throughout phylogeny. However, an HLA-A11 like gene in M. leucophaeus with a shortened C-terminal domain, and an HLA-A like orf in C. atys with two linked a1/a2/a3 domains, both contain a second transmembrane segment, which is conserved in Loc-103275158. Thus, we could model the putative protein with its Nef-like tail domain docked to its MHC-I like a3 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).5 Nef: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 the Loc-103275158 provisional 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 0 -tigger sequence encodes part of the pseudo a1/a2 MHC-I domain, and the 3 0 -tigger part of the Nef-like domain, we speculate that transposition proceeded phylogenetically disparate horizontal transfers, involving adjacent 5 0 -and 3 0 -parasitic footprints, which we also found in the Loc-103275158 orf.

Genome-wide transcriptome and translatome analyses reveal the role of protein extension and domestication in liver cancer oncogenesis

“…However, when talking about one “gene”, we do not refer to only one sequence. One gene could have different transcription start/termination sites (Soong et al 1994 ), translation start/termination sites (Kochetov et al 2005 ), alternative splicing patterns (Liu et al 2015 ), nucleotide modifications (Chandola et al 2015 ), protein modifications (Fung and Liu 2018 ), and even the switch between coding and non-coding genes, termed domestication (Murray and Murray 2016 ). All these factors and their combinations result in the endless isoforms of transcripts and protein sequences, even they are produced from the same gene.…”

Genome-wide transcriptome and translatome analyses reveal the role of protein extension and domestication in liver cancer oncogenesis

“…However, when talking about one "gene", we do not refer to only one sequence. One gene could have different transcription start/termination sites (Soong et al, 1994), translation start/termination sites (Kochetov et al, 2005), alternative splicing patterns (Liu et al, 2015), nucleotide modifications (Chandola et al, 2015), protein modifications (Fung and Liu, 2018), and even the switch between coding and non-coding genes, termed domestication (Murray and Murray, 2016). All these factors and their combinations result in the endless isoforms of transcripts and protein sequences, even they are produced from the same gene.…”

The Potential Mechanism of ZFX Involvement in the Cell Growth

“…Due to the presence of an acidic domain in ZFX protein, similar to the activation domain of transcription factors, and a potential nucleic acid-binding domain of 13 "zinc ringers", Palmer et al suggested that ZFX may be a plausible transcription facto (4). L'Haridon et al provided the first demonstration that the ZFX gene encodes a bona fide transcription factor (5). Zinn et al mapped one or more Turner syndrome traits, including short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease in a critical region in Xp11.2-p22.1 (6), implicating the importance of ZFX during game to genes is development and in efficient gametogenesis during adulthood (7).…”