Molecular evolution of NASP and conserved histone H3/H4 transport pathway

Abstract

BackgroundNASP is an essential protein in mammals that functions in histone transport pathways and maintenance of a soluble reservoir of histones H3/H4. NASP has been studied exclusively in Opisthokonta lineages where some functional diversity has been reported. In humans, growing evidence implicates NASP miss-regulation in the development of a variety of cancers. Although a comprehensive phylogenetic analysis is lacking, NASP-family proteins that possess four TPR motifs are thought to be widely distributed across eukaryotes.ResultsWe characterize the molecular evolution of NASP by systematically identifying putative NASP orthologs across diverse eukaryotic lineages ranging from excavata to those of the crown group. We detect extensive silent divergence at the nucleotide level suggesting the presence of strong purifying selection acting at the protein level. We also observe a selection bias for high frequencies of acidic residues which we hypothesize is a consequence of their critical function(s), further indicating the role of functional constraints operating on NASP evolution. Our data indicate that TPR1 and TPR4 constitute the most rapidly evolving functional units of NASP and may account for the functional diversity observed among well characterized family members. We also show that NASP paralogs in ray-finned fish have different genomic environments with clear differences in their GC content and have undergone significant changes at the protein level suggesting functional diversification.ConclusionWe draw four main conclusions from this study. First, wide distribution of NASP throughout eukaryotes suggests that it was likely present in the last eukaryotic common ancestor (LECA) possibly as an important innovation in the transport of H3/H4. Second, strong purifying selection operating at the protein level has influenced the nucleotide composition of NASP genes. Further, we show that selection has acted to maintain a high frequency of functionally relevant acidic amino acids in the region that interrupts TPR2. Third, functional diversity reported among several well characterized NASP family members can be explained in terms of quickly evolving TPR1 and TPR4 motifs. Fourth, NASP fish specific paralogs have significantly diverged at the protein level with NASP2 acquiring a NNR domain.

The H3 chaperone function of NASP is conserved in Arabidopsis

“…Among the putative H3.3 interactors, we noticed a tetratricopeptide (TRP)‐containing protein, which has so far not been functionally described in Arabidopsis. Sequence similarity to mammalian NASP has been reported before (Nabeel‐Shah et al ., ; Tripathi et al ., ). Mammalian NASP belongs to the N1/N2 family of chaperones (Gurard‐Levin et al ., ).…”

The histone chaperone sNASP binds a conserved peptide motif within the globular core of histone H3 through its TPR repeats

“…Sequence analysis of NASP and its orthologues has revealed three canonical TPR repeat motifs ( 29 , 31 , 36 – 37 ) and a putative TPR motif interrupted by a large acidic region ( 38 ), a TPR capping helix C-terminal to TPR4 and an unstructured C-terminal region ( 36 , 37 ). tNASP contains a 339 residue insertion within the acidic domain, compared to sNASP, caused by splicing in of exon 6 ( 36 , 39 ). The functional relevance of the two isoforms in humans is currently unclear.…”

Sex identification from distinctive gene expression patterns in Antarctic krill (Euphausia superba)

“…NASP is a histone chaperone involved in histone transport pathways, required for cell proliferation and widely distributed throughout eukaryotes (Richardson et al 2006;Nabeel-Shah et al 2014). NASP contains a tetratrico peptide repeat (TPR), which typically mediates protein-protein interactions.…”