Inhibition of Cullin RING Ligases by Cycle Inhibiting Factor: Evidence for Interference with Nedd8-Induced Conformational Control

Boh, Boon Kim; Ng, Mei Ying; Leck, Yee Chin; Shaw, Barry; Long, Jed; Sun, Guozhe; Gan, Yunn‐Hwen; Searle, Mark S.; Layfield, Robert; Hagen, Thilo

doi:10.1016/j.jmb.2011.08.030

Cited by 17 publications

(27 citation statements)

References 30 publications

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“…An overlay of NEDD8 in the Cif/NEDD8 complexes with neddylated Cul5 ctd -Rbx1 (16) shows it is unlikely that Cif can interact with neddylated cullins in a catalytically competent orientation (because of a significant clash), suggesting that Cifs deamidate NEDD8 before conjugation. Further, when Cif Bp is overexpressed in HEK293T cells with Cullin1, only very weak interaction is observed (22). Second, what is the precise mechanism by which NEDD8:Gln40 deamidation leads to stabilization of neddylated CRLs?…”

Section: Discussionmentioning

confidence: 99%

“…Second, what is the precise mechanism by which NEDD8:Gln40 deamidation leads to stabilization of neddylated CRLs? A recent study concluded that Cif-mediated NEDD8 deamidation inhibits CRL deneddylation by the COP9 signalosome (CSN) in vivo (22). This study proposed two mechanisms by which this could be achieved: (i) Deamidation of Gln40 prevents NEDD8-induced conformational changes in CRLs that are important for recognition by CSN, or (ii) deamidation of Gln40 directly inhibits recruitment of CSN to neddylated CRLs.…”

Section: Discussionmentioning

confidence: 99%

“…Significantly, Cif Ec was shown to inhibit the E3 ligase activity of neddylated cullins (7,9,20,21). Cif activity is correlated with accumulation of CRLs in their neddylated forms (22), preventing the neddylation/deneddylation cycle and locking CRLs in a neddylated but inactive form. This leads to stabilization of numerous CRL targets in cells, which presumably triggers the downstream cytopathic phenotype.…”

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confidence: 99%

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The molecular basis of ubiquitin-like protein NEDD8 deamidation by the bacterial effector protein Cif

Crow

Hughes

Taïeb

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The cycle inhibiting factors (Cifs) are a family of translocated effector proteins, found in diverse pathogenic bacteria, that interfere with the host cell cycle by catalyzing the deamidation of a specific glutamine residue (Gln40) in NEDD8 and the related protein ubiquitin. This modification prevents recycling of neddylated cullin-RING ligases, leading to stabilization of various cullin-RING ligase targets, and also prevents polyubiquitin chain formation. Here, we report the crystal structures of two Cif/NEDD8 complexes, revealing a conserved molecular interface that defines enzyme/substrate recognition. Mutation of residues forming the interface suggests that shape complementarity, rather than specific individual interactions, is a critical feature for complex formation. We show that Cifs from diverse bacteria bind NEDD8 in vitro and conclude that they will all interact with their substrates in the same way. The "occluding loop" in Cif gates access to Gln40 by forcing a conformational change in the C terminus of NEDD8. We used native PAGE to follow the activity of Cif from the human pathogen Yersinia pseudotuberculosis and selected variants, and the position of Gln40 in the active site has allowed us to propose a catalytic mechanism for these enzymes.bacterial pathogenesis | cyclomodulins | host cell manipulation | structural biology | type III secreted effector proteins

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The molecular basis of ubiquitin-like protein NEDD8 deamidation by the bacterial effector protein Cif

Crow

Hughes

Taïeb

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The Gln40Glu mutation in NEDD8 is sufficient to decrease the deneddylation rate by CSN in the absence of Cif (72). Gln40 is located close to the cullin-NEDD8 conjugation site.…”

Section: Deamidation Of Nedd8 By Cif Leads To Disruption Of the Ubiqumentioning

confidence: 98%

“…The deamidation of NEDD8 by Cif results in a reduction in the rate of cullin deneddylation (67,68,72). The Gln40Glu mutation in NEDD8 is sufficient to decrease the deneddylation rate by CSN in the absence of Cif (72).…”

Section: Deamidation Of Nedd8 By Cif Leads To Disruption Of the Ubiqumentioning

confidence: 99%

What a Difference a Dalton Makes: Bacterial Virulence Factors Modulate Eukaryotic Host Cell Signaling Systems via Deamidation

Washington

Banfield

Dangl

2013

Microbiol Mol Biol Rev

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SUMMARY Pathogenic bacteria commonly deploy enzymes to promote virulence. These enzymes can modulate the functions of host cell targets. While the actions of some enzymes can be very obvious (e.g., digesting plant cell walls), others have more subtle activities. Depending on the lifestyle of the bacteria, these subtle modifications can be crucially important for pathogenesis. In particular, if bacteria rely on a living host, subtle mechanisms to alter host cellular function are likely to dominate. Several bacterial virulence factors have evolved to use enzymatic deamidation as a subtle posttranslational mechanism to modify the functions of host protein targets. Deamidation is the irreversible conversion of the amino acids glutamine and asparagine to glutamic acid and aspartic acid, respectively. Interestingly, all currently characterized bacterial deamidases affect the function of the target protein by modifying a single glutamine residue in the sequence. Deamidation of target host proteins can disrupt host signaling and downstream processes by either activating or inactivating the target. Despite the subtlety of this modification, it has been shown to cause dramatic, context-dependent effects on host cells. Several crystal structures of bacterial deamidases have been solved. All are members of the papain-like superfamily and display a cysteine-based catalytic triad. However, these proteins form distinct structural subfamilies and feature combinations of modular domains of various functions. Based on the diverse pathogens that use deamidation as a mechanism to promote virulence and the recent identification of multiple deamidases, it is clear that this enzymatic activity is emerging as an important and widespread feature in bacterial pathogenesis.

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Landscape of ROD9 Island: Functional annotations and biological network of hypothetical proteins in Salmonella enterica

Soni

Swain

Kant

et al. 2019

Computational Biology and Chemistry

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Inhibition of Cullin RING Ligases by Cycle Inhibiting Factor: Evidence for Interference with Nedd8-Induced Conformational Control

Cited by 17 publications

References 30 publications

The molecular basis of ubiquitin-like protein NEDD8 deamidation by the bacterial effector protein Cif

The molecular basis of ubiquitin-like protein NEDD8 deamidation by the bacterial effector protein Cif

What a Difference a Dalton Makes: Bacterial Virulence Factors Modulate Eukaryotic Host Cell Signaling Systems via Deamidation

Landscape of ROD9 Island: Functional annotations and biological network of hypothetical proteins in Salmonella enterica

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