Targeting proteins for degradation

Abstract

Protein degradation plays a central role in many cellular functions. Misfolded and damaged proteins are removed from the cell to avoid toxicity. The concentrations of regulatory proteins are adjusted by degradation at the appropriate time. Both foreign and native proteins are digested into small peptides as part of the adaptive immune response. In eukaryotic cells, an ATP-dependent protease called the proteasome is responsible for much of this proteolysis. Proteins are targeted for proteasomal degradation by a two-part degron, which consists of a proteasome binding signal and a degradation initiation site. Here we describe how both components contribute to the specificity of degradation.

NOXA, a sensor of proteasome integrity, is degraded by 26S proteasomes by an ubiquitin-independent pathway that is blocked by MCL-1

“…31 Our findings do not exclude the possibility that NOXA turnover may occur by a trans inititation mechanism in vivo. 16 Consistent with this two-part degron model, 16 NOXA may associate with an uncharacterized polyubiquitinated adaptor protein that facilitates its targeting to the 19S RP and subsequently, degradation of NOXA is initiated from the unstructured region of NOXA. Further studies are necessary to distinguish this possibility from an alternative model that NOXA binds directly with sufficiently high affinity to the 19S RP, followed by degradation commencing from its unstructured region.…”

“…Various proteins, which can be degraded by an Ub-independent pathway, possess unstructured regions that may act as initiation sites for their subsequent degradation. 12,16 Multiple predictive tools suggested that the N-terminal region of NOXA has a high probability to be disordered (Supplementary Figure S4). Moreover, the thermal denaturation curve for synthetic NOXA (s-NOXA) showed no evidence of cooperative unfolding, which suggested that the protein was intrinsically unfolded, whereas DN-MCL-1-WT showed co-operative unfolding (Supplementary Figure S5A).…”

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

“…148 The rest of cohesin complex is apparently spared, owing to the subunit selectivity of the Arg/N-end rule pathway. 122,[234][235][236] The identity of a residue at the N-terminus of a C-terminal fragment of Scc1/Rad21 varies in a tellingly constrained manner. Specifically, this residue is Arg in the budding yeast S. cerevisiae, Asn in the fission yeast Schizosaccharomyces pombe, Cys in D. melanogaster, and Glu in mammals.…”

Cooperation between an Intrinsically Disordered Region and a Helical Segment Is Required for Ubiquitin-independent Degradation by the Proteasome

“…For ubiquitin-dependent degrons, the recognition/binding phase is accomplished by covalently attached polyubiquitin moieties that recognize one or more subunits of the proteasomal complex (46,47). For ubiquitin-independent degradation, mechanisms that directly involve the target substrate's polypeptide chain are utilized (12,18,44).…”

“…Mechanism of Degron Function-The currently accepted "two-component" model of proteasomal degradation posits two phases in degron function (45,46): (i) proteasome recognition and binding and (ii) initiation of insertion into the proteolytic chamber. For ubiquitin-dependent degrons, the recognition/binding phase is accomplished by covalently attached polyubiquitin moieties that recognize one or more subunits of the proteasomal complex (46,47).…”