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Topping off the proteasome

SBKB [doi:10.1038/sbkb.2011.67]
Featured Article - March 2012
Short description: The structure of the entire proteasome complex provides insight into key functions while raising questions for future studies.

Proteins are marked for degradation when they become damaged or misfolded, or when they are no longer needed by the cell. The proteasome is the primary complex responsible for protein degradation. The covalent attachment of a series of ubiquitin molecules to proteins enables the proteasome to recognize and degrade these doomed substrates. By controlling the levels of a multitude of proteins in the cell, the proteasome plays an important role in regulating key cellular processes such as the cell cycle and transcription, and is therefore a target for cancer therapeutics.

Negative-stain reconstruction of the holoenzyme shows locations of the core (grey), lid (yellow) and base (cyan). Figure courtesy of Andreas Martin.

A recent study by Martin and colleagues has revealed the structure of the entire proteasome holoenzyme by electron microscopy. While previous studies had defined the structure of the proteasomal proteolytic core, a barrel-shaped subcomplex into which unfolded substrates are fed for subsequent cleavage, there was limited structural information on the regulatory particle. This particle sits atop the proteolytic core, consists of a lid and a base subcomplex, and is responsible for substrate recognition, deubiquitination, unfolding, and translocation into the core.

The new structural information on the proteasome holoenzyme reveals the positions of the twelve non-ATPases of the regulatory particle, including the deubiquitinase Rpn11 found in the lid, as well as the six AAA+ ATPases of the base. The authors highlight several features of the structure which explain the mechanism for key functions of the regulatory particle while also raising questions that will influence future studies. For example, the structure reveals unexpected interactions between the lid and the core and between the lid and the motor domains of base subunits. The role of these interactions in the function of the proteasome remains to be determined. Other interactions, however, help explain the findings of previous functional studies on the proteasome. This is evident in the consistency of the spatial arrangement of the ubiquitin binding proteins and the deubiquitinase with studies indicating that a minimum of four K48-linked ubiquitins must be attached to the substrate for efficient degradation by the proteasome.

Jennifer Cable


  1. G. C. Lander et al. Complete subunit architecture of the proteasome regulatory particle.
    Nature. Published online 11 January 2012. doi:10.1038/10774

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