Recent advances in the structural biology of the 26S proteasome

Wehmer, Marc; Sakata, Eri

doi:10.1016/j.biocel.2016.08.008

Cited by 37 publications

(31 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Comparisons of Rpn11 active-site accessibility in the proteasome between different conformational states also revealed that the active site is occluded in the resting state of the proteasome but moves to a position over the ATPase outer-ring channel upon proteasome engagement with substrate[4,91,144]. This allows placement of the bond between the substrate and ubiquitin chain into the unobstructed Rpn11 active site as the substrate is threading through the ATPase pore, leading to amputation of the ubiquitin chain and continued substrate translocation.…”

Section: The Rp Lidmentioning

confidence: 99%

“…In the lid, the horseshoe-like structure formed by the winged-helix domains of the six PCI proteins cradles the MPN core of Rpn8/Rpn11 (Figures 7, 8a) [4,88,91,133,144]. The lid undergoes substantial conformational changes upon formation of the 26S proteasome, where it is splayed onto side of the Rpt3/Rpt6 base sector and makes contact with the CP as well[125].…”

Section: The Rp Lidmentioning

confidence: 99%

“…In eukaryotes, most regulated protein degradation is performed by the ubiquitin-proteasome system[1–4]. The concerted action of a series of enzymes activate and affix one or more ubiquitin moieties to a target protein[1,2].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Proteasome Structure and Assembly

Budenholzer

Cheng

et al. 2017

Journal of Molecular Biology

315

280

View full text Add to dashboard Cite

The eukaryotic 26S proteasome is a large multi-subunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be divided into two subcomplexes: the 19S regulatory particle (RP) and the 20S core particle (CP). Most substrates are first covalently modified by ubiquitin, which then directs them to the proteasome. The function of the RP is to recognize, unfold, deubiquitylate and translocate substrates into the CP, which contains the proteolytic sites of the proteasome. Given the abundance and subunit complexity of the proteasome, the assembly of this ~2.5 MDa complex must be carefully orchestrated to ensure its correct formation. In recent years, significant advances have been made in the understanding of proteasome assembly, structure and function. Technical advances in cryo-electron microscopy have resulted in a series of atomic cryo-EM structures of both human and yeast 26S proteasomes. These structures have illuminated new intricacies and dynamics of the proteasome. In this review, we focus on the mechanisms of proteasome assembly, particularly in light of recent structural information.

show abstract

Section: The Rp Lidmentioning

confidence: 99%

Section: The Rp Lidmentioning

confidence: 99%

See 1 more Smart Citation

Proteasome Structure and Assembly

Budenholzer

Cheng

et al. 2017

Journal of Molecular Biology

315

280

View full text Add to dashboard Cite

show abstract

“…38,45,47–49 The RPs contain receptors for ubiquitin recognition and will subsequently deubiquitinate, unfold, and transfer the substrate protein into the CP following ATP hydrolysis, as it proceeds through at least three major distinct conformational stages. 50,51 The degradation of ubiquitinated proteins requires one (19S–20S) or two regulatory particles (19S–20S–19S) to be docked onto the CP. 38,52 Not all additional modules require ATP hydrolysis to activate the 20S CP.…”

mentioning

confidence: 99%

Small Molecule Modulation of Proteasome Assembly

et al. 2018

View full text Add to dashboard Cite

The 20S proteasome is the main protease that directly targets intrinsically disordered proteins (IDPs) for proteolytic degradation. Mutations, oxidative stress, or aging can induce the buildup of IDPs resulting in incorrect signaling or aggregation, associated with the pathogenesis of many cancers and neurodegenerative diseases. Drugs that facilitate 20S-mediated proteolysis therefore have many potential therapeutic applications. We report herein the modulation of proteasome assembly by the small molecule TCH-165, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs, including α-synuclein, tau, ornithine decarboxylase, and c-Fos, but not structured proteins. Clearance of ubiquitinated protein was largely maintained by single capped proteasome complexes (19S–20S), but accumulation occurs when all 19S capped proteasome complexes are depleted. This study illustrates the first example of a small molecule capable of targeting disordered proteins for degradation by regulating the dynamic equilibrium between different proteasome complexes.

show abstract

“…During the dynamic process of (i) substrate accepting, (ii) commitment, and (iii) translocation three hypothetic conformational states of the yeast proteasome were distinguished by single particle cryo EM analysis (Figure 1) (Lander et al, 2013; Unverdorben et al, 2014). The translocation state might be dissected into more intermediates, since human proteasomes exist in at least four states during substrate processing (Wehmer and Sakata, 2016). …”

Section: Substrate Recognition By Poly-ubiquitylationmentioning

confidence: 99%

AAA-ATPases in Protein Degradation

Yedidi

Wendler

Enenkel

2017

Front. Mol. Biosci.

View full text Add to dashboard Cite

Proteolytic machineries containing multisubunit protease complexes and AAA-ATPases play a key role in protein quality control and the regulation of protein homeostasis. In these protein degradation machineries, the proteolytically active sites are formed by either threonines or serines which are buried inside interior cavities of cylinder-shaped complexes. In eukaryotic cells, the proteasome is the most prominent protease complex harboring AAA-ATPases. To degrade protein substrates, the gates of the axial entry ports of the protease need to be open. Gate opening is accomplished by AAA-ATPases, which form a hexameric ring flanking the entry ports of the protease. Protein substrates with unstructured domains can loop into the entry ports without the assistance of AAA-ATPases. However, folded proteins require the action of AAA-ATPases to unveil an unstructured terminus or domain. Cycles of ATP binding/hydrolysis fuel the unfolding of protein substrates which are gripped by loops lining up the central pore of the AAA-ATPase ring. The AAA-ATPases pull on the unfolded polypeptide chain for translocation into the proteolytic cavity of the protease. Conformational changes within the AAA-ATPase ring and the adjacent protease chamber create a peristaltic movement for substrate degradation. The review focuses on new technologies toward the understanding of the function and structure of AAA-ATPases to achieve substrate recognition, unfolding and translocation into proteasomes in yeast and mammalian cells and into proteasome-equivalent proteases in bacteria and archaea.

show abstract

Recent advances in the structural biology of the 26S proteasome

Cited by 37 publications

References 53 publications

Proteasome Structure and Assembly

Proteasome Structure and Assembly

Small Molecule Modulation of Proteasome Assembly

AAA-ATPases in Protein Degradation

Contact Info

Product

Resources

About