2.2. 20S proteasomes

1. Introduction

72 Current Understanding of Apoptosis - Programmed Cell Death

somes, and their substrates.

specific drug design to counterstrike cancer [3].

2. Ubiquitin proteasome system (UPS)

2.1. Ubiquitin conjugation and barcode properties

recognition, unfolding, and decay [6].

Posttranslational modification and regulated intracellular proteolysis are intimately linked with regulation of proliferation, differentiation, and apoptosis. Aforementioned survival processes depend on the steady-state levels of proteins acting as molecular switches of signaling networks and regulated proteolytic systems activating or removing such switches. Proteasomal protein degradation bifurcates into ubiquitin-dependent pathways, namely, the ubiquitin proteasome system (UPS) and ubiquitin-independent proteasomal protein (UIPP) degradation pathways [1]. Due to the modular structure of the proteasomal proteolytic system, composed of 20S proteasomes, 19S regulatory particles (RP), and 11S proteasome activator 28 (PA28) subtypes, it is challenging to identify definite relations between 20S proteasomes, regulator-associated protea-

Among 11S regulators, proteasome activator 28γ (PA28γ) has earned remarkable attention, due to its pronounced overexpression in cancer and its functional relation to tumor biology. Several evidences indicate that PA28γ, in addition to its role as a 20S proteasome activator and as a putative substrate recognition module, might also act as a modulator of E3 ubiquitin ligases. Since the first contributions of PA28γ to UIPP have been reviewed a decade ago [2], a reevaluation of proteasome biology with a focus on the intrinsic pathway of apoptosis seems justified. Growing knowledge about the remarkable efforts of various proteasomal proteolytic systems in cell survival will improve the mechanistic knowledge for target definition and

The discovery of the ubiquitin proteasome system seems to be a never ending story of surprise, starting with the first observations of non-lysosomal, ATP-dependent protein degradation [4], recognizing ubiquitin as a barcode label for proteins dedicated for proteasomal degradation [5] and, finally, realizing that ubiquitin labeling is not an absolute requirement for proteasomal

The enzymatic machinery-conjugating ubiquitin (Ub) or ubiquitin-like proteins (UBLs) to lysine is based on hundreds of enzymes, activators, inhibitors, and substrate adaptors, establishing an information-based system for multiple purposes in signal transduction. Fifteen human E1 enzymes (ubiquitin-activating enzymes (UBAs)) initiate the conjugation cascade either specifically using ubiquitin or one of the ten different UBLs as substrate. Thioesterlinked E1-Ub/UBL can be transferred to about 80 E2 enzymes (ubiquitin-conjugating UBC) via transesterification to the thiol group of an active site cysteine. Finally, more than 600 monomeric or multimeric E3 enzymes (ubiquitin protein ligases), either harboring RING or HECT domain motifs, constitute molecular scaffolds catalyzing the substrate-specific transfer
