Intrinsically Disordered Proteins: The Dark Horse of the Dark Proteome

Abstract

A good portion of the 'protein universe' embodies the 'dark proteome'. The latter comprises proteins not amenable to experimental structure determination by existing means and inaccessible to homology modeling. Hence, the dark proteome has remained largely unappreciated. Intrinsically disordered proteins (IDPs) that lack rigid 3D structure are a major component of this dark proteome across all three kingdoms of life. Despite lack of structure, IDPs play critical roles in numerous important biological processes. Furthermore, IDPs serve as crucial constituents of proteinaceous membrane-less organelles (PMLOs), where they often serve as drivers and controllers of biological liquid-liquid phase transitions responsible for the PMLO biogenesis. In this perspective, the role of IDPs is discussed in i) the origin of prebiotic life and the evolution of the first independent primordial living unit akin to Tibor Gánti's chemoton, which preceded the Last Universal Common Ancestor (LUCA), ii) role in multicellularity and hence, in major evolutionary transitions, and iii), their role in phenotypic switching, and the emergence of new traits and adaptive opportunities via non-genetic, protein-based mechanisms. The emerging picture suggests that despite being major constituents of the dark matter, IDPs may be the dark horse in the protein universe.

Computational Prediction of MoRFs, Short Disorder-to-order Transitioning Protein Binding Regions

“…Recent computational analyses estimate that about 30–50% of eukaryotic proteins (depending on the specific organism) have one or more long (having at least 30 consecutive residues) IDRs [ 4 , 5 ]. Intrinsic disorder is also one of the major factors that define dark proteomes [ 6 , 7 ]. The structural plasticity of IDRs facilitates efficient and promiscuous interactions with structurally distinct targets [ 8 , 9 ].…”

Intrinsically disordered proteins and structured proteins with intrinsically disordered regions have different functional roles in the cell

“…IDPs constitute, in eukaryotes, a substantial part of the 49 cellular proteome and are involved in many biological processes that complement the functional 50 repertoires of ordered proteins [9,10]. Ever-increasing experimental evidence has revealed the IDPs, allowing them to interact with a broad range of substrates with relatively high-specificity and 90 low-affinity, often undergoing a disorder-to-order transition upon binding [2,8,26,37,38]. However, 91 despite that this description makes sense for proteins lacking a tertiary structure (IDPs), it is 92 reasonable to suppose that structured proteins with long disordered regions (IDPRs) still interact 93 with substrates through a mechanism similar to the lock-and-key.…”

Memory effects in a random walk description of protein structure ensembles

“…One speaks here of intrinsically disordered proteins (IDP), where the term "disorder" describes the absence of well-defined secondary structure elements and may concern the whole protein or parts of it. [5][6][7][8] In contrast to well-structured proteins, for which more than 140000 structures can be found at present in the Protein Data Bank 9 , much less is known about the possible conformations of IDPs. Information comes here essentially from computer-generated models which are compatible with experimental data from structural NMR and small angle diffraction techniques.…”