Abstract
Intrinsically disordered regions (IDRs) of proteins play significant biological functional roles despite lacking a well-defined 3D structure. For example, IDRs provide efficient housing for large numbers of post-translational modification (PTM) sites in eukaryotic proteins. Here, we study the distribution of more than 15,000 experimentally determined human methylation, acetylation and ubiquitination sites (collectively termed ‘MAU’ sites) in ordered and disordered regions, and analyse their conservation across 380 eukaryotic species. Conservation signals for the maintenance and novel emergence of MAU sites are examined at 11 evolutionary levels from the whole eukaryotic domain down to the ape superfamily, in both ordered and disordered regions. We discover that MAU PTM is a major driver of conservation for arginines and lysines in both ordered and disordered regions, across the 11 levels, most significantly across the mammalian clade. Conservation of human methylatable arginines is very strongly favoured for ordered regions rather than for disordered, whereas methylatable lysines are conserved in either set of regions, and conservation of acetylatable and ubiquitinatable lysines is favoured in disordered over ordered. Notably, we find evidence for the emergence of new lysine MAU sites in disordered regions of proteins in deuterostomes and mammals, and in ordered regions after the dawn of eutherians. For histones specifically, MAU sites demonstrate an idiosyncratic significant conservation pattern that is evident since the last common ancestor of mammals. Similarly, folding-on-binding (FB) regions are highly enriched for MAU sites relative to either ordered or disordered regions, with ubiquitination sites in FBs being highly conserved at all evolutionary levels back as far as mammals. This investigation clearly demonstrates the complex patterns of PTM evolution across the human proteome and that it is necessary to consider conservation of sequence features at multiple evolutionary levels in order not to get an incomplete or misleading picture.
Highlights
Disordered regions (IDRs) in proteins were initially discovered as long stretches of amino acids in proteins that remain unfolded under physiological conditions [1, 2]
Disordered regions can house large numbers of post-translational modifications, such as the MAU sites which are the focus of this study
By examining for conservation of these sites in ordered and disordered regions separately, we have discovered that MAU is an important driver of arginine/lysine conservation throughout different stages of eukaryotic evolution, and that there is evolutionary evidence for key moments in human ancestry where new MAU sites have arisen in existing proteins, during the epochs of deuterostome and eutherian evolution
Summary
Disordered regions (IDRs) in proteins were initially discovered as long stretches of amino acids in proteins that remain unfolded under physiological conditions [1, 2]. IDRs can be functional despite this absence of a well-defined three-dimensional structure, and have caused a re-examination of the protein structure-function paradigm [1,2,3,4]. They are involved in numerous biological functions [2, 4,5,6,7,8] and their improper functioning leads to various disease conditions [7, 9,10,11]. Many computational tools have been developed to annotate disordered regions in amino acid sequences [16,17,18,19,20,21], facilitating the distinction between ordered and disordered regions
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