Alfred L. Goldberg in 1977 on ATP-dependent protein degradation in reticulocytes, which lack lysosomes, suggested the presence of a second intracellular degradation mechanism. This was shown in 1978 to be composed of several distinct protein chains, a novelty among proteases at the time. Later work on modification of histones led to the identification of an unexpected covalent modification of the histone protein by a bond between a lysine side chain of the histone and the C-terminal glycine residue of ubiquitin, a protein that had no known function. It was then discovered that a previously identified protein associated with proteolytic degradation, known as ATP-dependent proteolysis factor 1 (APF-1), was the same protein as ubiquitin. The proteolytic activities of this system were isolated as a multi-protein complex originally called the multi-catalytic proteinase complex by Sherwin Wilk and Marion Orlowski. Later, the ATP-dependent proteolytic complex that was responsible for ubiquitin-dependent protein degradation was discovered and was called the 26S proteasome. Much of the early work leading up to the discovery of the ubiquitin proteasome system occurred in the late 1970s and early 1980s at the Technion in the laboratory of Avram Hershko, where Aaron Ciechanover worked as a graduate student. Hershko's year-long sabbatical in the laboratory of Irwin Rose at the Fox Chase Cancer Center provided key conceptual insights, though Rose later downplayed his role in the discovery. The three shared the 2004 Nobel Prize in Chemistry for their work in discovering this system. Although electron microscopy data revealing the stacked-ring structure of the proteasome became available in the mid-1980s, the first structure of the proteasome core particle was not solved by X-ray crystallography until 1994. In 2018, the first atomic structures of the human 26S proteasome holoenzyme in complex with a polyubiquitylated protein substrate were solved by cryogenic electron microscopy, revealing mechanisms by which the substrate is recognized, deubiquitylated, unfolded and degraded by the human 26S proteasome. Structure and organization The proteasome subcomponents are often referred to by their Svedberg sedimentation coefficient (denoted S). The proteasome most exclusively used in mammals is the cytosolic 26S proteasome, which is about 2000 kilodaltons (kDa) in molecular mass containing one 20S protein subunit and two 19S regulatory cap subunits. The core is hollow and provides an enclosed cavity in which proteins are degraded; openings at the two ends of the core allow the target protein to enter. Each end of the core particle associates with