Common schema of ubiquitination
Common schema of ubiquitination Modulation of protein activity by ubiquitin-dependent modification regulates theturnover, degradation and function of many cellular proteins. Ubiquitin-activating enzyme(E1), ubiquitin-conjugating enzyme (E2), and ubiquitin ligase (E3) catalyze the reactionof conjugation of the Ubiquitin protein moiety to a variety of biologicallysignificant protein substrates for targeted degradation through the 26S proteasome, aswell as for non-proteolytic regulation of their functions or subcellular localizations, . Ubiquitin is first attached to E1 ubiquitin-activating enzyme UBE1 in anATP -dependent manner. The activated Ubiquitin is then transferred to E2ubiquitin-conjugating enzyme, such as UBE2A, UBE2C, UBE2V2 ( MMS2), UBCH6, UBE2E2, UBE2D1, UBE2D2, UBE2D3 andUBE2H. E3 ubiquitin ligase, such as Cul5/Rbx1 E3 ligase complex,Cul5/Rbx2 E3 ligase complex, APC/CDC20 complex, APC/hCDH1 complex,UBE3A, MDM2, HUWE1, Itch, Parkin, RAD18,NEDD4, c-Cbl and SMURF, recognizes the protein substrate, recruitsE2-ubiquitin complex, and catalyzes Ubiquitin transfer from E2 to substrate. Asingle run of the reaction causes monoubiquitination of the target protein that canchange its function, whereas multiple runs of the reaction lead to polyubiquitination ofthe substrate. Depending on ubiquitin-ubiquitin linkage, polyubiquitinated proteins caneither be activated (through K63 linkage), or recognized and degraded by the 26Sproteasome (through K48 linkage) . A group of enzymes collectively termed deubiquitinating enzymes catalyzes thehydrolysis of the isopeptide linkage that joins the C-terminal glycine ofUbiquitin and a lysine side chain on the target polypeptide. This enzyme familyconsists of four structurally distinct subfamilies, including the Ubiquitin C-terminalhydrolases, such as Ubiquitin carboxyl-terminal esterase L3 ( UCHL3 ) and BRCA1associated protein-1 ( BAP1 ) that hydrolyzes small C-terminal adducts ofubiquitin to generate the Ubiquitin monomer , ,.