Protein Expansion Is Primarily due to Indels in Intrinsically Disordered Regions

Abstract

Proteins evolve not only through point mutations but also by insertion and deletion events, which affect the length of the protein. It is well known that such indel events most frequently occur in surface-exposed loops. However, detailed analysis of indel events in distantly related and fast-evolving proteins is hampered by the difficulty involved in correctly aligning such sequences. Here, we circumvent this problem by first only analyzing homologous proteins based on length variation rather than pairwise alignments. Using this approach, we find a surprisingly strong relationship between difference in length and difference in the number of intrinsically disordered residues, where up to three quarters of the length variation can be explained by changes in the number of intrinsically disordered residues. Further, we find that disorder is common in both insertions and deletions. A more detailed analysis reveals that indel events do not induce disorder but rather that already disordered regions accrue indels, suggesting that there is a lowered selective pressure for indels to occur within intrinsically disordered regions.

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.…”

Pipeline to Identify Hydroxyproline-Rich Glycoproteins

“…IDPs do not conform to the structurefunction paradigm, as they are highly mobile, lack a persistent structure, and yet are stable (Schlessinger et al, 2011;Szalkowski and Anisimova, 2011;FormanKay and Mittag, 2013;Light et al, 2013). Fully sequenced eukaryotic proteomes suggest that IDPs are common, with 10% to 20% of proteins being completely disordered and 25% to 40% being partially disordered (Ward et al, 2004;Oates et al, 2013;Peng et al, 2014;Kurotani and Sakurai, 2015).…”

Computational prediction of the tolerance to amino-acid deletion in green-fluorescent protein

“…10 By contrast, the fundamental properties governing protein tolerance to indel events 11 are comparatively understudied. Previous efforts in comparative sequence analysis have 12 suggested that indels preferentially occur in disordered and/or loop regions and are less 13 common in regions with secondary structure [11][12][13][14][15]. Furthermore, indel events may be 14 more likely to occur on the protein surface, where residues are more exposed to solvent, 15 rather than in a protein's core [13,14].…”

“…Previous efforts in comparative sequence analysis have 12 suggested that indels preferentially occur in disordered and/or loop regions and are less 13 common in regions with secondary structure [11][12][13][14][15]. Furthermore, indel events may be 14 more likely to occur on the protein surface, where residues are more exposed to solvent, 15 rather than in a protein's core [13,14]. Thus, constraints on indel events appear to 16 mirror those on substitution events, in that amino-acid substitutions are most frequent 17 in unstructured regions and on the protein surface [1].…”