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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

The Human Immunodeficiency Virus Type 1 Vpu Protein Inhibits NF-κB Activation by Interfering with βTrCP-mediated Degradation of IκB

TL;DR: It is suggested that Vpu modulates both virus- and cytokine-induced activation of NF-κB in HIV-1-infected cells and has a dominant negative effect on TrCP function.
Journal ArticleDOI

Specific small molecule inhibitors of Skp2-mediated p27 degradation.

TL;DR: This work identified small molecule inhibitors specific to SCF-Skp2 activity using in silico screens targeted to the binding interface for p27 that selectively inhibited Skp2-mediated p27 degradation by reducing p27 binding through key compound-receptor contacts.
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Identification of SCF ubiquitin ligase substrates by global protein stability profiling.

TL;DR: The established and applied genetic technologies that combine global protein stability profiling and genetic perturbation of E3 activity to screen for substrates of the Skp1–cullin–F-box (SCF) ubiquitin ligase in mammalian cells found most known SCF targets and many previously unknown substrates involved in cell cycle, apoptosis, and signaling pathways.
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mTOR Generates an Auto-Amplification Loop by Triggering the βTrCP- and CK1α-Dependent Degradation of DEPTOR

TL;DR: The findings reveal that mTOR cooperates with CK1α and βTrCP to generate an auto-amplification loop to promote its own full activation, and suggest that pharmacologic inhibition of CK1 may be a viable therapeutic option for the treatment of cancers characterized by activation of mTOR-signaling pathways.
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Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis

TL;DR: The results suggest that Fbxw7 regulates the cell cycle in a differentiation-dependent manner, with its loss resulting in c-Myc accumulation that leads to hyperproliferation in immature T cells but to p53-dependent cell-cycle arrest and apoptosis in mature T cells.
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