Proteasome structure and function
The proteasome is a large, highly conserved protein complex whose main function is to enzymatically degrade target proteins. The eukaryotic proteasome houses six protease sites that are located deep within the barrel-shaped 20S core particle. Each core particle is built from two outer rings formed from seven alpha subunits, and two inner rings formed from seven beta subunits. The N-termini of the alpha subunit rings on either end of the core particle form a gate which can open to allow passage of target proteins into the proteasome core.
Gate opening is regulated by association with the 19S regulatory particle (RP), which is composed of two major parts: a lid and a base. The base is made up of six ATPases which form a ring. The C-terminal tails of the ATPases fit into "pockets" in the core particle, causing a conformational change and resulting in gate opening.
How the heptameric core particle and hexameric base interact is not well understood. The "wobble" hypothesis suggests that the regulatory particle may rock back and forth while bound to the core particle, such that only a subset of C-terminal tails in the base associate with the pockets in the core particle at any given moment. This hypothesis is illustrated in the animation on the lower right.
In eukaryotes, proteins are tagged for degradation with chains of proteins known as ubiquitin. The ubiquitin tag is recognized by subunits in the lid of the proteasome, and is thought to be eventually removed as the target protein enters the proteasome for degradation. Meanwhile, the protein unfolds and enters the central channel and is cleaved into short peptides of 3 to 15 amino acids in length. These peptides eventually exit the proteasome through one or both open pores.
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Proteasome Structure
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Proteasome Mechanism
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Proteasome Rocking
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Acknowledgements
Many thanks to Alfred Goldberg and David Smith (Havard Medical School) for collaborating on this project.
