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| Title | Systemwide disassembly and assembly of SCF ubiquitin ligase complexes. |
|---|---|
| Journal, issue, pages | Cell, Vol. 186, Issue 9, Page 1895-1911.e21, Year 2023 |
| Publish date | Apr 27, 2023 |
 Authors | Kheewoong Baek / Daniel C Scott / Lukas T Henneberg / Moeko T King / Matthias Mann / Brenda A Schulman /   |
| PubMed Abstract | Cells respond to environmental cues by remodeling their inventories of multiprotein complexes. Cellular repertoires of SCF (SKP1-CUL1-F box protein) ubiquitin ligase complexes, which mediate much ...Cells respond to environmental cues by remodeling their inventories of multiprotein complexes. Cellular repertoires of SCF (SKP1-CUL1-F box protein) ubiquitin ligase complexes, which mediate much protein degradation, require CAND1 to distribute the limiting CUL1 subunit across the family of ∼70 different F box proteins. Yet, how a single factor coordinately assembles numerous distinct multiprotein complexes remains unknown. We obtained cryo-EM structures of CAND1-bound SCF complexes in multiple states and correlated mutational effects on structures, biochemistry, and cellular assays. The data suggest that CAND1 clasps idling catalytic domains of an inactive SCF, rolls around, and allosterically rocks and destabilizes the SCF. New SCF production proceeds in reverse, through SKP1-F box allosterically destabilizing CAND1. The CAND1-SCF conformational ensemble recycles CUL1 from inactive complexes, fueling mixing and matching of SCF parts for E3 activation in response to substrate availability. Our data reveal biogenesis of a predominant family of E3 ligases, and the molecular basis for systemwide multiprotein complex assembly. |
 External links | Cell / PubMed:37028429 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.7 - 9.4 Å |
| Structure data | EMDB-14561, PDB-7z8r: EMDB-14563, PDB-7z8t: EMDB-14564, PDB-7z8v: EMDB-14594, PDB-7zbw: EMDB-14597, PDB-7zbz:  EMDB-14598: CAND1 delhairpin-SCF-SKP2 CAND1 rolling SCF engaged  EMDB-14599: CAND1-SCF-FBXW7 CAND1 rolling-1a  EMDB-14600: CAND1-SCF-FBXW7 CAND1 rolling-1b  EMDB-14601: CAND1-SCF-FBXW7 CAND1 rolling-2c  EMDB-14602: CAND1-SCF-FBXW7 CAND1 rolling-2d  EMDB-14603: CAND1-SCF-FBXW7 CAND1 rolling-2a  EMDB-14604: CAND1-SCF-FBXW7 CAND1 rolling-2b  EMDB-14605: CAND1-SCF-FBXW7 CAND1 little CAND1  EMDB-14606: CAND1-SCF-FBXW7 CAND1 no CAND1-1  EMDB-14607: CAND1-SCF-FBXW7 CAND1 no CAND1-2  EMDB-14608: CAND1-SCF-FBXW7 (SKP1deldel) CAND1 engaged no SKP1-Fbp  EMDB-14609: CAND1-SCF-FBXW7 (SKP1deldel) CAND1 engaged SCF rocked  EMDB-14610: CAND1delhairpin-SCF-FBXW7 CAND1 partly engaged SCF partly rocked  EMDB-14611: CAND1delhairpin-SCF-FBXW7 CAND1 rolling-2d SCF engaged  EMDB-14612: CAND1delhairpin-SCF-FBXW7 CAND1 rolling-2c SCF engaged  EMDB-14613: CAND1delhairpin-SCF-FBXW7 CAND1 rolling-2b SCF engaged  EMDB-14614: CAND1delhairpin-SCF-FBXW7 CAND1 rolling-2a SCF engaged  EMDB-14615: CAND1(2X)-SCF-FBXW7 no CAND1 SCF engaged  EMDB-14616: CAND1(2X)-SCF-FBXW7 CAND1 rolling-1 SCF engaged EMDB-16575, PDB-8cdj: EMDB-16576, PDB-8cdk:  EMDB-16577: CAND1(2X)-SCF-FBXW7 CAND1 rolling-2 SCF engaged  EMDB-16578: CAND1(2X)-SCF-FBXW7 CAND1 engaged SCF rocked  EMDB-16579: CAND1-SCF-FBXW7 no CAND1 SCF engaged (low res)  EMDB-16580: CAND1-SCF-FBXW7 CAND1 rolling-1 SCF engaged (low res)  EMDB-16581: CAND1-SCF-FBXW7 CAND1 rolling-2 SCF engaged (low res)  EMDB-16582: CAND1-SCF-SKP2 CAND1 rolling-1 SCF engaged  EMDB-16583: CAND1-SCF-SKP2 CAND1 rolling-2 SCF engaged (low res)  EMDB-16584: CAND1-SCF-SKP2 CAND1 engaged SCF rocked (low res)  EMDB-16585: CAND1-SCF-FBXO6 no CAND1 SCF engaged  EMDB-16586: CAND1-SCF-FBXO6 CAND1 rolling-1 SCF engaged  EMDB-16587: CAND1-SCF-FBXO6 CAND1 rolling-2 SCF engaged  EMDB-16588: CAND1-SCF-FBXO6 CAND1 engaged SCF rocked  EMDB-16589: CAND1-SCF-FBXO6 CAND1 engaged no SKP1-Fbp  EMDB-16617: CAND1-SCF-SKP2 with substrate p27-CKSHS1-CyclinA-CDK2, CAND1 engaged SCF rocked  EMDB-16621: CAND1-SCF-SKP2 with substrate p27-CKSHS1-CyclinA-CDK2, CAND1 rolling SCF engaged  EMDB-16622: CAND1-SCF-SKP2 with substrate p27-CKSHS1, CAND1 engaged SCF rocked  EMDB-16623: CAND1-SCF-SKP2 with substrate p27-CKSHS1, CAND1 rolling SCF engaged  EMDB-16625: CAND1-SCF-SKP2 with substrate p27-CKSHS1-CyclinA-CDK2, no CAND1 SCF engaged  EMDB-16764: CAND1delb-hairpin CUL1-RBX1 CAND1 partly engaged  EMDB-16765: CAND1delb-hairpin CUL1-RBX1 CAND1 rolling-1  EMDB-16766: CAND1delb-hairpin CUL1-RBX1 CAND1 rolling-2 |
| Chemicals |  ChemComp-ZN: |
| Source |
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 Keywords |  LIGASE / cullin-RING E3 ubiquitin ligase / Assembly factor / CAND1 / SCF |
