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  • The two major families of E ubiquitin

    2020-08-08

    The two major TMP269 of E3 ubiquitin ligases (see Glossary) that coordinate cell division are SCFs (SKP1–CUL1–Fbox proteins), which were initially recognized for regulating interphase and are now known to control many stages of the cell cycle, and anaphase-promoting complex/cyclosome (APC/C), which regulates mitosis, the exit from mitosis, and G1 (reviewed in 1, 2, 3, 4, 5, 6). APC/C also regulates sequential progression through other stepwise processes, including meiosis, differentiation, morphogenesis, and migration of various postmitotic neuronal cell types (reviewed in 7, 8, 9, 10). To understand mechanisms orchestrating temporal regulation of biological processes such as cell division, it is important to understand how E3 ligases ubiquitylate their substrates. Both SCFs and APC/C belong to the so-called cullin-RING ligase (CRL) superfamily, due to their catalytic cores containing both Cullin and RING ligase subunits. Common features of CRLs include: (i) substrate degron sequences are recruited to variable substrate-receptor subunits that associate interchangeably with a dynamic cullin–RING catalytic core; and (ii) a specific cullin–RING core recruits and activates a transient thioester-bonded complex between Ub and another enzyme (typically an E2), from which Ub is transferred to the remotely bound substrate (typically forming an isopeptide bond between the C terminus of Ub and a substrate lysine) 11, 12. While SCF E3 ligase activity was reconstituted with recombinant proteins two decades ago, the ability to probe APC/C was limited until recently because of its behemoth size. Human APC/C is a 1.2-MDa assembly comprised of 19 core subunits (one each of nine different APC subunits, and two each of five), which catalyzes ubiquitylation in collaboration with an additional coactivator protein and a Ub-linked E2 conjugating enzyme (Figure 1A and Box 1) (reviewed in 13, 14, 15). The variable substrate receptors are CDC20 and CDH1, which are termed coactivators due to their successively activating APC/C during mitosis by both recruiting substrates 16, 17, 18 and conformationally activating the catalytic core 19, 20, 21 (Figure 1). The catalytic core consists of the cullin and RING subunits APC2 and APC11 22, 23, 24. The APC2–APC11 cullin–RING assembly directs Ub transfer from an assortment of E2 enzymes with different specificities 25, 26, 27. Repeated cycles of Ub transfer lead to polyubiquitylation, wherein multiple individual Ubs become linked to the substrate and to each other to form Ub chains. There is enormous diversity in the architecture of potential Ub chains produced by APC/C, with the number of Ubs, and the sites of their chain linkages, thought to influence the rates of substrate degradation by the proteasome. The E2 enzyme UBE2C/UBCH10 (or in some circumstances the E2 UBE2D/UBCH5 [28]) directly modifies substrates with one or more Ubs or short Ub chains (reviewed in 13, 14, 15), which are sufficient to target some human APC/C substrates for degradation [29]. However, many substrates are degraded after a different E2 enzyme, UBE2S in humans 30, 31, 32, extends a poly-Ub chain. Ub is transferred from the catalytic cysteine UBE2S to Lys11 on a Ub that is already attached to a substrate. Often, branched chains are formed when UBE2C first modifies a substrate with Lys48-linked Ub chains, and then UBE2S further extends these chains with additional Ubs connected via Lys11. These Lys48/Lys11 branched chains are particularly potent at directing substrates for proteasomal degradation [33].