Structural basis for dynamic regulation of the human 26S proteasome

The proteasome holoenzyme is an ATP-dependent protease in eukaryotes that degrades ubiquitylated substrates. It is involved in numerous important biological processes, such as cell division, differentiation, innate immunity, adaptive immunity, regulation of gene expression, and response to proteotoxic stress. Using cryoelectron microscopy, we have examined multiple conformational states of the human proteasome at medium to high resolution. Our results reveal that the substrate-conducting channel in the core particle is transiently opened and accompanied by dynamic changes in structure of the particle. These observations provide new insights into how the proteasome recognizes ubiquitylated substrates and translocates them through a channel and gate to degradation sites in the core particle.