TY - JOUR
T1 - Mechanism of Ψ-Pro/C-degron recognition by the CRL2FEM1B ubiquitin ligase
AU - Chen, Xinyan
AU - Raiff, Anat
AU - Li, Shanshan
AU - Guo, Qiong
AU - Zhang, Jiahai
AU - Zhou, Hualin
AU - Timms, Richard T.
AU - Yao, Xuebiao
AU - Elledge, Stephen J.
AU - Koren, Itay
AU - Zhang, Kaiming
AU - Xu, Chao
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/4/26
Y1 - 2024/4/26
N2 - The E3 ligase-degron interaction determines the specificity of the ubiquitin‒proteasome system. We recently discovered that FEM1B, a substrate receptor of Cullin 2-RING ligase (CRL2), recognizes C-degrons containing a C-terminal proline. By solving several cryo-EM structures of CRL2FEM1B bound to different C-degrons, we elucidate the dimeric assembly of the complex. Furthermore, we reveal distinct dimerization states of unmodified and neddylated CRL2FEM1B to uncover the NEDD8-mediated activation mechanism of CRL2FEM1B. Our research also indicates that, FEM1B utilizes a bipartite mechanism to recognize both the C-terminal proline and an upstream aromatic residue within the substrate. These structural findings, complemented by in vitro ubiquitination and in vivo cell-based assays, demonstrate that CRL2FEM1B-mediated polyubiquitination and subsequent protein turnover depend on both FEM1B-degron interactions and the dimerization state of the E3 ligase complex. Overall, this study deepens our molecular understanding of how Cullin-RING E3 ligase substrate selection mediates protein turnover.
AB - The E3 ligase-degron interaction determines the specificity of the ubiquitin‒proteasome system. We recently discovered that FEM1B, a substrate receptor of Cullin 2-RING ligase (CRL2), recognizes C-degrons containing a C-terminal proline. By solving several cryo-EM structures of CRL2FEM1B bound to different C-degrons, we elucidate the dimeric assembly of the complex. Furthermore, we reveal distinct dimerization states of unmodified and neddylated CRL2FEM1B to uncover the NEDD8-mediated activation mechanism of CRL2FEM1B. Our research also indicates that, FEM1B utilizes a bipartite mechanism to recognize both the C-terminal proline and an upstream aromatic residue within the substrate. These structural findings, complemented by in vitro ubiquitination and in vivo cell-based assays, demonstrate that CRL2FEM1B-mediated polyubiquitination and subsequent protein turnover depend on both FEM1B-degron interactions and the dimerization state of the E3 ligase complex. Overall, this study deepens our molecular understanding of how Cullin-RING E3 ligase substrate selection mediates protein turnover.
UR - http://www.scopus.com/inward/record.url?scp=85191626162&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-47890-5
DO - 10.1038/s41467-024-47890-5
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C2 - 38670995
AN - SCOPUS:85191626162
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3558
ER -