Structural Basis of the Cks1-Dependent Recognition of p27Kip1 by the SCFSkp2 Ubiquitin Ligase

Hao, Bing; Zheng, Ning; Schulman, Brenda A.; Wu, Geng; Miller, Julie J.; Pagano, Michele; Pavletich, Nikola P.

doi:10.1016/j.molcel.2005.09.003

Cited by 251 publications

(248 citation statements)

References 60 publications

(59 reference statements)

Supporting

Mentioning

244

Contrasting

Order By: Relevance

“…Fbxws utilize the WD40 domain to interact with phosphorylated linear degradation sequences; however in the case of the Fbxls, the leucine zipper motif is contacting a larger surface and could require the presence of cofactors (Hao et al , 2005; Xing et al , 2013). The conformation of Sufu is regulated by Gli binding and Sufu–Gli interaction requires an intact tertiary structure of Sufu (Cherry et al , 2013; Zhang et al , 2013).…”

Section: Resultsmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

View full text Add to dashboard Cite

Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

show abstract

Section: Resultsmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In the case of CRL1 Tir1 -auxin, binding of auxin to the substrate receptor Tir1 creates a surface on the ligase that mediates binding to and ubiquitylation of its substrates (45). Although ubiquitylation of the CRL1 Skp2 substrate p27 requires prior formation of a complex between the substrate receptor Skp2 and its cofactor Cks1, this interaction is not the initiating event to trigger p27 destruction (46,47). Rather, CRL1 Skp2 -Cks1-mediated proteolysis is promoted by a phosphorylation event on threonine 187 of the substrate p27, which mediates the p27-CRL1 Skp2 -Cks1 interaction (3,46,49 (27) and therefore almost certainly precedes binding of the ligase.…”

Section: Discussionmentioning

confidence: 99%

Direct Role for Proliferating Cell Nuclear Antigen in Substrate Recognition by the E3 Ubiquitin Ligase CRL4Cdt2

Havens

Shobnam

Guarino

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: CRL4Cdt2 requires that a substrate bind to proliferating cell nuclear antigen (PCNA) on DNA prior to ligase recruitment, but the precise role of PCNA is unclear. Results: A specific PCNA residue is required for destruction of CRL4 Cdt2 substrates. Conclusion: CRL4Cdt2 recognizes a composite surface composed of PCNA and substrate residues. Significance: This is the first ubiquitin ligase whose substrate recognition requires creation of a bipartite substrate surface.

show abstract

“…A C-terminal deletion mutant of Skp2 that lacks the last 175 amino acids, including the last five leucine-rich domains of the substrate-binding site, and is thus unable to recruit substrates (25,26) was found to associate almost exclusively with unneddylated Cul1 (Fig. 5).…”

Section: The Stimulation Of Cullin Neddylation By Adapter and Substramentioning

confidence: 99%

Substrate-mediated Regulation of Cullin Neddylation

Chew¹,

Hagen

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Cullin-based E3 ligases are a large family of multi-subunit ubiquitin ligases with diverse cellular functions, including the regulation of the cell cycle, of the DNA damage response, and of various transcription factors. These ligases are composed of one of six mammalian cullin homologs (Cul1, Cul2, Cul3, Cul4a, Cul4b, and Cul5), the Ring finger containing protein Roc1/ Rbx1, and cullin homolog-specific adaptor and substrate recognition subunits. To be active, cullin-based ligases require the covalent modification of a conserved lysine residue in the cullin protein with the ubiquitin-like protein Nedd8. We show in this study that in intact cells Cul1 neddylation is dependent on binding to adaptor proteins and substrate recognition subunits. Mutant Cul1 that is unable to recruit adaptor and substrate recognition subunits exhibits markedly reduced neddylation, and inhibiting binding of adaptor and substrate recognition subunits to wild type Cul1 reduces Nedd8 modification. This regulatory mechanism also extends to other cullin-based E3 ligases, including Cul2, Cul3, and Cul4a. The regulation of cullin neddylation by adaptor proteins and substrate recognition subunits in cells was found to be independent of both CAND1 and the COP9 signalosome, two negative regulators of cullin Nedd8 modification. Using hypoxia-inducible factor-1␣ (HIF-1␣), a substrate of the Elongin B/C-Cul2-VHL ligase, we demonstrate the critical role of substrate binding to promote Cul2 neddylation in a manner that does not require substrate ubiquitination but may involve a conformational change. These findings suggest a mechanism through which availability of substrate recognition subunits and substrates can regulate the ubiquitin ligase activity. Cullin-based E33 ligases comprise a large family of ubiquitin ligases that mediate the ubiquitination of numerous cellular proteins with diverse functions including roles in cell signaling, transcriptional regulation, and cell cycle control (1). They are RING domain-containing ligases that function by binding the substrate through a protein-protein interaction domain and the E2 enzyme through the RING motif, thus bringing substrate and E2 enzyme into close proximity and facilitating the transfer of ubiquitin molecules to lysine residues in the substrate. Cullin-based E3 ligases are composed of several subunits, consisting of one of six mammalian cullin homologs (Cul1, Cul2, Cul3, Cul4a, Cul4b, and Cul5) that binds to the RING domain protein Roc1/Rbx1 via its C terminus. The cullin N terminus mediates binding of cullin homolog-specific substrate recognition subunits. Binding of the substrate recognition subunits requires specific adaptor proteins that bridge the interaction with the cullin homologs (except in the case of Cul3). For instance, Cul1 is known to bind substrate recognition subunits containing a conserved F-box via the adaptor protein Skp1, thus forming SCF (Skp1-Cul1-F-box) E3 ligases, whereas Cul2 and Cul5 recruit substrate recognition subunits with a VHL or SOCS box, respectively, via the ...

show abstract

Structural Basis of the Cks1-Dependent Recognition of p27Kip1 by the SCFSkp2 Ubiquitin Ligase

Cited by 251 publications

References 60 publications

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

Direct Role for Proliferating Cell Nuclear Antigen in Substrate Recognition by the E3 Ubiquitin Ligase CRL4Cdt2

Substrate-mediated Regulation of Cullin Neddylation

Contact Info

Product

Resources

About