19SRegulatoren

The 19S regulatory particle, also known as the 19S regulator of the proteasome, is the regulatory cap of the 26S proteasome in eukaryotic cells. It binds to the 20S core particle and governs substrate recognition, deubiquitination, unfolding, and translocation into the proteolytic chamber.

Traditionally organized into a base and a lid, the regulator forms a bipartite structure. The base contains six AAA+ ATPase subunits (Rpt1–Rpt6) and associated non-ATPase subunits that assemble into a ring capable of substrate unfolding. The lid harbors non-ATPase subunits that include ubiquitin receptors and a deubiquitinase, notably Rpn11, which removes ubiquitin chains before degradation. The particle recognizes polyubiquitinated substrates via the receptors and presents them for processing.

Mechanistically, substrate binding via ubiquitin receptors initiates deubiquitination by Rpn11, followed by opening of the gate on the 20S core particle. The ATPase ring threads the unfolded substrate into the catalytic chamber, where proteolysis occurs.

Regulation and dynamics: The 19S regulator is a dynamic entity that assembles with the 20S core and can form alternative proteasome complexes under different cellular conditions. Its activity is modulated by post-translational modifications and interactions with cofactors, and it cooperates with other regulators in specialized degradation pathways.

Significance: The 19S regulator is essential for most ubiquitin-dependent proteolysis in eukaryotic cells. Dysfunctions in proteasome regulation have been linked to neurodegenerative diseases and cancer. Therapeutic strategies often target the proteasome system, including proteasome inhibitors, while research continues on modulators that specifically affect the 19S regulator.