3.2.2. Proteasomal Degradation

Intrinsically disordered proteins undergo proteasomal degradation through two different (but not mutually exclusive) pathways, ubiquitin-dependent (UD) and ubiquitin-independent (UI) [211]. The UD pathway relies on the addition of ubiquitin to the substrate to be degraded, in a process regulated by a series of enzymes and is mediated collectively by the 26S proteasome [212]. It was found that IDPs present a high content of predicted ubiquitination sites [185,205], and, in an analysis

of ubiquitinated proteins, there seems to be a correlation between confirmed degradation sites and regions of disorder [213]. Alternatively, the UI pathway is mainly orchestrated by the core of the 20S proteasome, being a default process for degradation of free disordered proteins. Some evidences support the hypothesis that the flexible and extended structures of IDPs (as well as disordered terminal segments in folded proteins) facilitates the interaction with the proteasome, considering that bulky particles have reduced cleavage rates [214,215].

### 3.2.3. Stabilization through "Nanny" Proteins

As IDPs are usually prone to degradation, there is a need for protein stabilization in some contexts. The ubiquitous enzyme NQO1 functions as a "gatekeeper" of the 20S proteasomes, binding and regulating the degradation of some IDPs, in a mechanism consuming NADH [211,216]. An analogous mechanism characterizes the "nanny" model for IDP protection from cleavage, where there is sequestration of ID segments by interactions with other proteins, resulting in evasion from 20S proteasomal digestion. The binding of the nanny is transient, beginning at the initial stage of IDPs' life cycle, when they are newly synthesized (assuming they are more sensible to digestion in this stage) [154]. Despite the fact that nanny proteins also bind to nascent polypeptide chains, they are not considered chaperones because they do not induce a fixed three-dimensional organization on targets, only assisting on IDP conservation without permanently affecting their disordered structure.
