Structural basis for the activation of 20S proteasomes by 11S regulators

Most of the non-lysosomal proteolysis that occurs in eukaryotic cells is pe rformed by a nonspecific and abundant barrel-shaped complex called the 20S proteasome(1). Substrates access the active sites, which are sequestered in an internal chamber, by traversing a narrow opening(2) (alpha -annulus) th at is blocked in the unliganded 20S proteasome by amino-terminal sequences of alpha -subunits(3). Peptide products probably exit the 20S proteasome th rough the same opening. 11S regulators (also called PA26 (ref. 4), PA28 (re f. 5) and REG(6,7)) are heptamers(4,8,9) that stimulate 20S proteasome pept idase activity in vitro and may facilitate product release in vivo. Here we report the co-crystal structure of yeast 20S proteasome with the 11S regul ator from Trypanosoma brucei 4 (PA26). PA26 carboxy-terminal tails provide binding affinity by inserting into pockets on the 20S proteasome, and PA26 activation loops induce conformational changes in alpha -subunits that open the gate separating the proteasome interior from the intracellular environ ment. The reduction in processivity expected for an open conformation of th e exit gate may explain the role of 11S regulators in the production of lig ands for major histocompatibility complex class I molecules(10,11).