The ubiquitin-proteasome pathway. The substrate proteins are designated for degradation by conjugation to ubiquitin in an ATP-dependent reaction. The ubiquitin-activating enzyme (E1) uses ATP to create a highly reactive thiolester form of ubiquitin, and then transfers it to a ubiquitin-carrier protein (E2). The subsequent transfer of the activated ubiquitin to the protein substrate requires a ubiquitin-protein ligase (E3). The E3 ligases muscle atrophy F-box (MAFbox) and muscle ring finger-1 (MuRF-1) have important roles in skeletal muscle atrophy. Once the ubiquitin conjugates are formed, they are transported to a proteolytic complex known as the 26S proteasome, consisting of two 19S regulators and the 20S core proteasome. The 19S regulators recognize and bind the ubiquitinated protein. Energy from ATP hydrolysis releases the ubiquitin chain and unfolds the substrate protein. The unfolded protein is fed into the 20S proteasome for degradation into small peptides and amino acids. The 20S proteasome can degrade oxidized protein without ubiquitination. Adapted with permission from .