Context‐dependent resistance to proteolysis of intrinsically disordered proteins

Abstract

Intrinsically disordered proteins (IDPs), also known as intrinsically unstructured proteins (IUPs), lack a well-defined 3D structure in vitro and, in some cases, also in vivo. Here, we discuss the question of proteolytic sensitivity of IDPs, with a view to better explaining their in vivo characteristics. After an initial assessment of the status of IDPs in vivo, we briefly survey the intracellular proteolytic systems. Subsequently, we discuss the evidence for IDPs being inherently sensitive to proteolysis. Such sensitivity would not, however, result in enhanced degradation if the protease-sensitive sites were sequestered. Accordingly, IDP access to and degradation by the proteasome, the major proteolytic complex within eukaryotic cells, are discussed in detail. The emerging picture appears to be that IDPs are inherently sensitive to proteasomal degradation along the lines of the ''degradation by default'' model. However, available data sets of intracellular protein half-lives suggest that intrinsic disorder does not imply a significantly shorter half-life. We assess the power of available systemic half-life measurements, but also discuss possible mechanisms that could protect IDPs from intracellular degradation. Finally, we discuss the relevance of the proteolytic sensitivity of IDPs to their function and evolution.

Paradoxes and wonders of intrinsic disorder: Stability of instability

“…59 This structural instability is supported by the well-known fact of high sensitivity of IDPs/IDPRs to proteolytic degradation. [68][69][70][71][72][73][74][75][76][77] High resilience of intrinsic disorder Although lacking stable structure, possessing noncooperative unfolding behavior, and showing high sensitivity to proteolysis, one of the most intriguing biophysical properties ascribed to highly disordered proteins is their extraordinary resilience, where an IDP can sustain exposure to the extremely harsh environmental conditions, being able either to keep its functionality under these extreme conditions or to rapidly regain it after returning to normal conditions. 48,49 An illustrative example of such behavior is given by a "funny protein" prothymosin a, 48 which triggered my interest to the intrinsically disordered proteins by its unusual ability to be unharmed by the prolonged exposure to harsh conditions (activity of the protein was not affected by boiling for a few days).…”

Dual life of TPPP/p25 evolved in physiological and pathological conditions

“…We established that the proteasome machinery is the main, if not exclusive, degrading system responsible for the elimination of the disordered unbound TPPP/p25 [26,31] as described for many intrinsically unstructured proteins [32][33][34]. Their degradations are inhibited by MG132, a well-established inhibitor of proteasome, which further suggests the involvement of the proteasome machinery in their degradation [32].…”

Paradigms of protein degradation by the proteasome

“…There is some evidence from bioinformatics studies that proteins that contain intrinsically disordered regions have on average shorter half-lives than proteins lacking these regions [50,51] but so far the evidence for this relationship is not consistent. Other studies do not find these correlations [52-54] and there is some evidence that ubiquitination sites of proteasome substrates are preferentially located in unstructured regions [55,56]. Even when the unstructured region is not found in a substrate protein, ubiquitination itself may induce the local unfolding near the ubiquitinated residue, which, in turn, could create an initiation site for the proteasome [57].…”