Sequence- and Species-Dependence of Proteasomal Processivity

The proteasome is the degradation machine at the center
of the
ubiquitin-proteasome system and controls the concentrations of many
proteins in eukaryotes. It is highly processive so that substrates
are degraded completely into small peptides, avoiding the formation
of potentially toxic fragments. Nonetheless, some proteins are incompletely
degraded, indicating the existence of factors that influence proteasomal
processivity. We have quantified proteasomal processivity and determined
the underlying rates of substrate degradation and release. We find
that processivity increases with species complexity over a 5-fold
range between yeast and mammalian proteasome, and the effect is due
to slower but more persistent degradation by proteasomes from more
complex organisms. A sequence stretch that has been implicated in
causing incomplete degradation, the glycine-rich region of the NFκB
subunit p105, reduces the proteasome’s ability to unfold its
substrate, and polyglutamine repeats such as found in Huntington’s
disease reduce the processivity of the proteasome in a length-dependent
manner.