Abstract
Proteins are highly dynamic entities. Their myriad functions require specific structures, but proteins’ dynamic nature ranges all the way from the local mobility of their amino acid constituents to mobility within and well beyond single cells. A truly comprehensive view of the dynamic structural proteome includes: (i) alternative sequences, (ii) alternative conformations, (iii) alternative interactions with a range of biomolecules, (iv) cellular localizations, (v) alternative behaviors in different cell types. While these aspects have traditionally been explored one protein at a time, we highlight recently emerging global approaches that accelerate comprehensive insights into these facets of the dynamic nature of protein structure. Computational tools that integrate and expand on multiple orthogonal data types promise to enable the transition from a disjointed list of static snapshots to a structurally explicit understanding of the dynamics of cellular mechanisms.
Highlights
The human genome sequence has a smaller number of genes than expected: ß19 000 compared to 6.7 million genes in earlier estimates [1]
We focus on recently developed methodologies designed to study dynamic protein conformations, interactions, and subcellular mobility
While the contribution of NMR to solving new structures might shrink in the future, it cannot be over-emphasised that this technique has unique capabilities in covering directly a large range of protein solution dynamics on timescales ranging from picoseconds to hours [49]
Summary
(ii) Alternative splicing has been implicated in tissue differentiation and is positively correlated with organism complexity [3,4,5]. (iv) Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) can assume alternative secondary and tertiary conformations. This expands the available space of alternative structures [9]. To cope with this phenomenon, it was recently suggested to extend the concept of “proteoforms” to include manifold alternative conformations of IDPs and IDRs as “conformational (or basic or intrinsic) proteoforms” [23]. Increasing largely anecdotal evidence suggests that both transient and persistent structural disorder play crucial roles in biology and understanding disease mechanisms and that there is no unique disordered state but rather a continuum from fully structured to fully disordered [34, 35]
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