Since first imaged by electron microscopy, much effort has been placed into determining the structure and mechanism of the 26S proteasome. While the proteolytic core is understood in atomic detail, how substrates are engaged and transported to this core remains elusive. Substrate delivery is accomplished by a 19-subunit regulatory particle that binds to ubiquitinated substrates, detaches ubiquitin tags, unfolds the substrate, and translocates it into the peptidase in an ATP-dependent fashion. Recently, several labs have determined subnanometer cryoEM structures of the 26S proteasome, shedding light on the architecture of the regulatory complex. We discuss the biological insights into substrate processing provided by these structures, and the technical hurdles ahead to achieve an atomic resolution structure of the 26 proteasome.
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