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Mechanisms and function of substrate recruitment by F-box proteins

Nature Reviews Molecular Cell Biology volume 14, pages 369–381 (2013)Cite this article

Subjects

Key Points

  • F-box proteins are the substrate-targeting subunits of S phase kinase-associated protein 1 (SKP1)–cullin 1 (CUL1)–F-box protein (SCF) ubiquitin ligase complexes. In mammals, approximately 70 F-box proteins, each able to target multiple substrates, enable SCF complexes to control the levels of many regulatory proteins with diverse functions.

  • F-box protein substrates are recognized through degradation motifs (degrons). The best-characterized F-box proteins recognize conserved consensus degron sequences that include phosphorylated amino acids (phosphodegrons).

  • Although phosphodegrons remain the most common mechanism of substrate recognition by F-box proteins, many additional degron recognition mechanisms, both dependent on or independent of post-translational modifications, can facilitate substrate targeting.

  • Because an individual F-box protein can regulate the degradation of multiple substrates, it can control multiple different pathways in response to various different stimuli. Therefore, F-box proteins can have context-dependent functions, including functions that may seem contradictory.

  • The activity of F-box proteins can also be controlled directly through several mechanisms, including localization, expression and degradation.

  • F-box proteins have key roles in cell regulatory mechanisms, and they are frequently dysregulated in diseases. Historically, the F-box protein family has been examined in the context of cancer, but these proteins have emerging roles in a wide range of other diseases.

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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Figure 1: The cullin–RING ligase family.
Figure 2: Recognition of substrates by F-box proteins.
Figure 3: Dysregulation of F-box protein-mediated degradation in disease.
Figure 4: Generalized and context-dependent functions of F-box proteins.

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Acknowledgements

The authors apologize to their colleagues in the field for omitting their work owing to space constraints. J.R.S. is a Special Fellow of The Leukemia and Lymphoma Society. J.K.P. is supported by a fellowship from the Lymphoma Research Foundation. Work in the Pagano laboratory is supported by grants from the US National Institutes of Health (NIH) (R37CA076584 and R01GM057587). M.P. is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Pathology, New York University Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, 10016, New York, USA

    Jeffrey R. Skaar & Julia K. Pagan

  2. Department of Pathology, Howard Hughes Medical Institute, New York University Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, 10016, New York, USA

    Michele Pagano

Authors
  1. Jeffrey R. Skaar
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  3. Michele Pagano
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Correspondence to Jeffrey R. Skaar or Michele Pagano.

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Glossary

Ubiquitin

A 76-amino-acid protein that can be covalently conjugated to Lys residues in other proteins to specify several protein fates. Polyubiquitin chains can be generated using seven internal Lys residues in ubiquitin. Lys11- or Lys48-linked chains target proteins to the proteasome, whereas other chains, such as Lys63-linked chains, have signalling roles. Monoubiquitylation also has a signalling role.

RING

Really interesting new gene (RING) proteins coordinate zinc using Cys and His residues in a cross-brace arrangement. RING proteins typically recruit E2 ubiquitin-conjugating enzymes.

NEDD8

A small ubiquitin-like protein that can be covalently conjugated to other proteins. Cullin proteins are the primary targets for neddylation, which activates the cullin–RING ligase.

Degrons

Small sections of a substrate that are recognized by a ubiquitin ligase and that are required for substrate degradation. Canonical degrons for F-box proteins are very short, conserved stretches of amino acids.

β-transducin repeat-containing protein

(βTrCP). Refers to two paralogous F-box proteins, βTrCP1 (FBXW1 (F-box and WD40 domain 1)) and βTrCP2 (FBXW11), that are biochemically indistinguishable. βTrCP recognizes phosphodegrons through WD40 repeats.

Cyclin-dependent kinase

(CDK). These are drivers of the cell cycle. The activity of these kinases is controlled by the availability of their cognate cyclins. The oscillation of cyclin levels during the cell cycle determines which CDKs are active.

αβ-crystallin

A chaperone protein that can be induced by heat, but unlike heat shock proteins, it does not re-fold proteins. Instead, αβ-crystallin forms protein aggregates.

Cyclin-homology domain

This domain normally determines the binding of cyclins to cyclin-dependent kinase substrates. The original cyclins were identified on the basis of their cyclic oscillations, but additional proteins contain a cyclin-homology domain, which has led to their designation as cyclins.

Ribonucleotide reductase subunit M2

(RRM2). A subunit of the enzyme that converts ribonucleotides to deoxyribonucleotides for DNA replication. RRM2 is regulated by the cell cycle, whereas the RRM1 subunit is stable throughout the cell cycle.

Isoprenylation

The transfer of a farnesyl or geranyl–geranyl moiety to a carboxy-terminal Cys residue of a target protein. This modification facilitates protein recruitment to membranes.

RAB3-interacting molecule 1

(RIM1). It is expressed near the active zone of the neuronal synapse and interacts with many presynaptic proteins, including RAB3. It controls calcium-evoked neurotransmitter release.

Auxin

A family of plant hormones required for growth signalling. Indole-3-acetic acid is the most potent auxin. They bind to TRANSPORT INHIBITOR RESPONSE 1, a plant F-box protein, promoting its interaction with auxin–indoleacetic acid transcriptional repressors.

Jasmonate

A lipid-based plant hormone that binds to CORONATINE-INSENSITIVE 1, an F-box protein, and JA–ZIM domain (JAZ), a transcriptional regulator, promoting the degradation of JAZ.

Checkpoint kinase 1

(CHK1). A Ser/Thr kinase that is required for checkpoint arrest and DNA repair following DNA damage.

CDT2

A DDB1- and CUL4-associated factor (DCAF) protein that mediates the degradation of SET domain-containing protein 8, p21 and CDT1, preventing re-replication in S phase.

Cryptochrome 1 and cryptochrome 2

(CRY1 and CRY2). Mammalian CRY proteins function as transcriptional repressors within a negative feedback loop of the circadian cycle. CLOCK and BMAL1 activate the transcription of genes encoding period (PER) and CRY proteins, which then negatively regulate transcription by CLOCK–BMAL1. In lower organisms, CRY proteins function as photoreceptors, but this activity is not present in mammals.

p100

An inhibitor of nuclear factor-κB (NF-κB) signalling and the precursor for p52, which forms an active transcription factor in conjunction with REL family proteins. p100 is part of the non-canonical NF-κB signalling pathway, which largely responds to developmental signals.

Bortezomib

A proteasome inhibitor approved as frontline therapy for multiple myelomas. Originally, much of its effectiveness was ascribed to inhibition of canonical nuclear factor-κB signalling through stabilization of inhibitor of κB proteins.

DEPTOR

(DEP-domain containing mTOR-interacting protein). An inhibitor of the mammalian target of rapamycin (mTOR) kinase in the context of both mTOR complex 1 (mTORC1) and mTORC2.

Mammalian target of rapamycin

(mTOR). A PI3K that is an important regulator of cell growth and metabolism, particularly protein synthesis. mTOR forms two complexes, designated mTOR complex 1 (mTORC1) and mTORC2, which have multiple feedback links.

Telomere length regulation protein 2 and TELO2-interacting protein 1

(TEL2 and TTI1). Evolutionarily conserved proteins that interact with all six mammalian PI3K-like protein kinases and control their abundance.

Familial advanced sleep phase syndrome

An inherited circadian and sleep disorder in which patients have altered circadian rhythms, with early sleep onset and early waking.

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Skaar, J., Pagan, J. & Pagano, M. Mechanisms and function of substrate recruitment by F-box proteins. Nat Rev Mol Cell Biol 14, 369–381 (2013). https://doi.org/10.1038/nrm3582

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