Long indels are disordered: A study of disorder and indels in homologous eukaryotic proteins

Abstract

This is an accepted version of a paper published in Biochimica et Biophysica ActaProteins and Proteomics. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination.Citation for the published paper: Light, S., Sagit, R., Ekman, D., Elofsson, A. (2013) "Long indels are disordered: A study of disorder and indels in homologous eukaryotic proteins" Biochimica et Biophysica Acta -Proteins and Proteomics, 1834(5): 890-897 Access to the published version may require subscription. AbstractProteins evolve through point mutations as well as by insertions and deletions (indels). During the last decade it has become apparent that protein regions that do not fold into three-dimensional structures, i.e. intrinsically disordered regions, are quite common. Here, we have studied the relationship between protein disorder and indels using HMM-HMM pairwise alignments in two sets of orthologous eukaryotic protein pairs. First, we show that disordered residues are much more frequent among indel residues than among aligned residues and, also are more prevalent among indels than in coils. Second, we observed that disordered residues are particularly common in longer indels. Disordered indels of short-to-medium size are prevalent in the nonterminal regions of proteins while the longest indels, ordered and disordered alike, occur toward the termini of the proteins where new structural units are comparatively well tolerated. Finally, while disordered regions often evolve faster than ordered regions and disorder is common in indels, there are some previously recognized protein families where the disordered region is more conserved than the ordered region. We find that these rare proteins are often involved in information processes, such as RNA processing and translation.

Nucleotide Insertions and Deletions Complement Point Mutations to Massively Expand the Diversity Created by Somatic Hypermutation of Antibodies

“…Significant mutation of framework regions and pronounced use of indels suggest that immune responses to these challenging antigens (1, 14 -16, 39, 40) often require significant remodeling of regions peripheral to the combining site center. Previous analysis of non-IgG protein structures found that indel residues are disordered and preferentially occur in regions of increased disorder tolerant to accommodating new sequences (41)(42)(43)(44)(45)(46). This work extends previous reports demonstrating the importance of secondary mechanisms in antibody diversification beyond V(D)J recombination and AID-mediated single nucleotide mutations.…”

Intrinsically Disordered Segments Affect Protein Half-Life in the Cell and during Evolution

“…These include repeat expansion, alternative splicing, and alternative transcription start sites, all of which can influence the length of terminal and/or internal disorder of protein products, thereby potentially influencing the half-life. This idea is supported by the observation that protein disorder is common in insertions and deletions (Light et al, 2013). Furthermore, given that in multicellular eukaryotes (1) alternative transcription start sites commonly generate variation in N termini (Carninci et al, 2006) and (2) alternatively spliced exons are enriched in intrinsic disorder (Buljan et al, 2013), it is likely that such events that generate diversity in protein sequences in different cell types within an individual will have an effect on protein half-life.…”

Evolution of Protein Domain Repeats in Metazoa

“…Disordered regions often evolve faster than structured regions (Dosztányi et al 2010; Szalkowski and Anisimova 2011; Light et al 2013a). The consequential strong divergence at the sequence level could explain why most largely disordered domain repeat families cannot be matched to any domain HMM in Pfam or SUPERFAMILY.…”