The SOCS Box Domain of SOCS3: Structure and Interaction with the ElonginBC-Cullin5 Ubiquitin Ligase

Babon, Jeffrey J.; Sabo, Jennifer K.; Soetopo, Alfreda; Yao, Shenggen; Bailey, Michael F.; Zhang, Jianguo; Nicola, Nicos A.; Norton, Raymond S.

doi:10.1016/j.jmb.2008.06.038

Cited by 88 publications

(104 citation statements)

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“…Modeling of C. elegans ELC‐1 and human TCEB1, a homolog of elongin C, was performed by using SWISS‐MODEL (http://swissmodel.expasy.org/) (Biasini et al ., 2014), based on the crystal structures of mammalian VHL–elongin C–elongin B complex and SOCS3–elongin B–elongin C complex (Stebbins et al ., 1999; Babon et al ., 2008). Structures were revisualized and aligned using PyMOL (http://www.pymol.org/) (Schrodinger, 2010).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

et al. 2015

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SummaryThe transcription factor hypoxia‐inducible factor 1 (HIF‐1) is crucial for responses to low oxygen and promotes longevity in Caenorhabditis elegans. We previously performed a genomewide RNA interference screen and identified many genes that act as potential negative regulators of HIF‐1. Here, we functionally characterized these genes and found several novel genes that affected lifespan. The worm ortholog of elongin C, elc‐1, encodes a subunit of E3 ligase and transcription elongation factor. We found that knockdown of elc‐1 prolonged lifespan and delayed paralysis caused by impaired protein homeostasis. We further showed that elc‐1 RNA interference increased lifespan and protein homeostasis by upregulating HIF‐1. The roles of elongin C and HIF‐1 are well conserved in eukaryotes. Thus, our study may provide insights into the aging regulatory pathway consisting of elongin C and HIF‐1 in complex metazoans.

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Section: Methodsmentioning

confidence: 99%

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

et al. 2015

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“…Purification consisted of nickel affinity, anion exchange, His tag removal, and gel filtration. Murine Cul5 N-terminal domain (NTD) was purified as previously described (1). Briefly, Cul5 NTD was expressed in E. coli BL21(DE3) cells from pGEX-4T-1 overnight at 18°C by induction with 0.5 mM IPTG.…”

Section: Methodsmentioning

confidence: 99%

Dissection of the HIV Vif Interaction with Human E3 Ubiquitin Ligase

Wolfe

Stanley

Liu

et al. 2010

J Virol

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The human immunodeficiency virus type 1 (HIV-1) protein Vif recruits the host E3 ubiquitin ligase, composed of cullin 5 (Cul5), Rbx2, Elongin B, and Elongin C (EloBC), to polyubiquitinate the antiviral protein APOBEC3G. Multiple regions in the C-terminal half of Vif interact with the E3 ligase. We have purified individual regions of Vif and investigated their thermodynamic contributions to the ligase assembly in vitro using isothermal titration calorimetry and fluorescence anisotropy. Our results quantify the high-affinity interactions between the Vif BC box and EloBC and between the Vif zinc finger and Cul5, as well as the modest interaction between the Vif cullin box and Cul5. Our purified Vif constructs also provide direct biochemical evidence that the Vif cullin box, containing the PPLP region, leads to the dimerization of Vif-EloBC complexes but not Cul5-Vif-EloBC complexes.HIV Vif antagonizes the human antiviral protein APOBEC3G by hijacking the human Elongin B/C (EloBC)-cullin-SOCS box (ECS)-type E3 ubiquitin ligase, resulting in the polyubiquitination of APOBEC3G and subsequently its proteasomal degradation. Canonical ECS-type ubiquitin ligases consist of a cullin scaffold protein to which adaptor and substrate receptor proteins bind at the N terminus. HIV Vif serves as a substrate receptor protein-its N terminus recruits APOBEC3G, while multiple C-terminal regions assemble with the E3 ligase (9, 13, 24). The E3 ligase interacting regions include a zinc finger (residues 100 to 140), a BC box (residues 141 to 154), and a cullin box (residues 155 to 176) ( Fig. 1).Vif binds the cullin adaptor proteins EloB and EloC through the BC-box region (24). The BC box is a loop-helix motif with the consensus sequence (T/S)LxxxCxxx(V/L/I) (7), and it also exists in cellular proteins that interact with EloBC. While Vif does not fit this consensus perfectly, it still binds EloBC with high affinity, and this interaction is lost upon mutation or deletion of consensus BC-box residues (10,24,25). This interaction has been described previously for the cellular proteins VHL (15), SOCS2 (3), SOCS3 (1), SOCS4 (4), and recently HIV Vif (14).Both the Vif zinc finger and cullin box interact with the E3 ligase scaffold protein cullin 5 (Cul5) (11,12,20,21). It has been established that the zinc finger is required for Vif to bind Cul5. Mutation of critical histidine or cysteine residues in this region or the addition of the zinc chelator N,N,NЈ,NЈ-tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN) abolishes the Vif-Cul5 interaction (8,11,25). The sequence of the Vif cullin box is not as conserved as those of cellular SOCS-box proteins, which have a defined structure and determine the specificities of their respective cullins (6). The role of the Vif cullin box is not clear, but it has been suggested to promote dimerization of Vif, involving the conserved PPLP region (22, 23), and has recently been implicated in APOBEC3G binding (5, 17). While its importance in Cul5 binding has been demonstrated in coimmunoprecipitation experiments (14...

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“…The BCbox is a conserved N-terminal region of 12 residues, which recruits elongins B and C and relies critically on a highly conserved leucine in the 14 position (14,16,17). When bound to elongins B and C, the SOCS box forms three a-helices (H1-H3); helix 4 of elongin C (H4) packs against the SOCS box to form a four-a-helical bundle, making hydrophobic contacts with the conserved leucine and cysteine of the BC-box (L163 and C167 in SOCS2), whereas elongin B acts to stabilise the complex and has only minimal interaction with the SOCS box itself ( Fig.…”

Section: Socs Box-mediated Ubiquitinationmentioning

confidence: 99%

“…It has now been shown that the SOCS box is only partially folded in the absence of elongins B and C and that their presence is required to stabilise the protein (16). Indeed, the increased stability of the trimeric complex has aided production of soluble recombinant SOCS box proteins, facilitating the elucidation of the SOCS2 and SOCS4 crystal structures (18,20).…”

Section: Socs Box-mediated Ubiquitinationmentioning

confidence: 99%

The SOCS box—Adapting proteins for ubiquitination and proteasomal degradation

2012

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SummaryThe suppressor of cytokine signalling (SOCS) box was first identified in the SH2-containing SOCS box family (cytokine-inducible SH2-containing protein, SOCS1-7) and is a 40-amino acid motif, which functions to recruit an E3 ubiquitin ligase complex consisting of the adapter proteins elongins B and C, Rbx2 and the scaffold protein Cullin5. The SOCS box is found in a diverse array of intracellular signalling molecules, many of which contain different protein interaction domains such as SPRY and WD40 domains, leucine and ankyrin repeats or other functional domains such as GTPases. In general, the SOCS box-containing proteins are thought to act as substrate-recognition modules to mediate the polyubiquitination and subsequent degradation of substrate proteins by the 26S proteasome.

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The SOCS Box Domain of SOCS3: Structure and Interaction with the ElonginBC-Cullin5 Ubiquitin Ligase

Cited by 88 publications

References 50 publications

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

Inhibition of elongin C promotes longevity and protein homeostasis via HIF‐1 in C. elegans

Dissection of the HIV Vif Interaction with Human E3 Ubiquitin Ligase

The SOCS box—Adapting proteins for ubiquitination and proteasomal degradation

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