The 19S Proteasome is a multi-subunit regulatory particle that associates with the 20S Proteasome core particle to form the 26S Proteasome. The 19S Proteasome can cap the 20S Proteasome at one or both ends and regulate substrate access to proteolytic activity in an ATP-dependent manner by modulating the conformation of the 20S Proteasome and facilitating substrate access to the 20S Proteasome catalytic core.

​

The 19S Proteasome recognizes ubiquitinated proteins as well as non-ubiquitinated, misfolded proteins. It catalyzes substrate deubiquitination, unfolds substrate proteins, and threads them into the 20S Proteasome catalytic core.

​

The 19S Proteasome consists of a base subcomplex and a lid subcomplex. The base subcomplex is composed of six AAA+ family members, two scaffolding proteins, and regulatory proteins involved in Ubiquitin recognition. The 19S Proteasome lid subcomplex contains eight subunits and one deubiquitinating enzyme, Rpn11.

​

Although inhibitors targeting the 19S Proteasome regulatory particle have been developed, they are underutilized in comparison with proteasome inhibitors targeting the 20S Proteasome core particle.