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Mechanisms and function of substrate recruitment by F-box proteins

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TLDR
The evolution of substrate recruitment by F-box proteins, the dysregulation of substrates in disease and potential avenues for F- box protein-directed disease therapies are focused on.
Abstract
S phase kinase-associated protein 1 (SKP1)-cullin 1 (CUL1)-F-box protein (SCF) ubiquitin ligase complexes use a family of F-box proteins as substrate adaptors to mediate the degradation of a large number of regulatory proteins involved in diverse processes The dysregulation of SCF complexes and their substrates contributes to multiple pathologies In the 14 years since the identification and annotation of the F-box protein family, the continued identification and characterization of novel substrates has greatly expanded our knowledge of the regulation of substrate targeting and the roles of F-box proteins in biological processes Here, we focus on the evolution of our understanding of substrate recruitment by F-box proteins, the dysregulation of substrate recruitment in disease and potential avenues for F-box protein-directed disease therapies

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Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx/atrogin-1

TL;DR: This review will focus on the current understanding of MuRF1 and MAFbx in skeletal muscle, highlighting the critical questions that remain to be answered.
Journal ArticleDOI

Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide

TL;DR: The studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN while the ligase complex is recruiting IKZF1 or IKzF3 for degradation, which implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.
Journal ArticleDOI

New insights into ubiquitin E3 ligase mechanism

TL;DR: E3 ligases carry out the final step in the ubiquitination cascade, catalyzing transfer of ubiquitin from an E2 enzyme to form a covalent bond with a substrate lysine.
References
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Journal ArticleDOI

Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex

TL;DR: It is shown that the F-box protein Skp2 is polyubiquitinated, and hence earmarked for destruction, by APCCDH1, and accumulation of SCFSKP2 requires prior inactivation of APCC DH1.
Journal ArticleDOI

SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins

TL;DR: It is found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCFFbxl3 ubiquitin ligase complex, a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity.
Journal ArticleDOI

The cell-cycle regulatory protein Cks1 is required for SCF Skp2 -mediated ubiquitinylation of p27

TL;DR: It is shown that the missing factor is CDK subunit 1 (Cks1), which belongs to the highly conserved Suc1/Cks family of proteins that bind to some CDKs and phosphorylated proteins and are essential for cell-cycle progression.
Journal ArticleDOI

Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase.

TL;DR: The induction of Skp2 and Cks1 degradation in G1 represents a principal mechanism by which APC/CCdh1 prevents the unscheduled degradation of SCFSkp2–Cks1 substrates and maintains the G1 state.
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