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Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.

Deuquet J, Lausch E, Guex N, Abrami L, Salvi S, Lakkaraju A, Ramirez MC, Martignetti JA, Rokicki D, Bonafe L, Superti-Furga A, van der Goot FG - EMBO Mol Med (2011)

Bottom Line: Through the analysis of four patients, we identify three novel mutants and determine their effects at the cellular level.Mutations in the Ig-like domain prevent proper disulphide bond formation and are more efficiently targeted to ER-associated degradation.Finally, we show that mutant CMG2 can be rescued in fibroblasts of some patients by treatment with proteasome inhibitors and that CMG2 is then properly transported to the plasma membrane and signalling competent, identifying the ER folding and degradation pathway components as promising drug targets for HFS.

View Article: PubMed Central - PubMed

Affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.

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Related in: MedlinePlus

Model of the ectodomain of CMG2Basic representation of the CMG2 protein and its domains, highlighting the positions of the seven cysteines and HFS mutations analysed in this study.Structural model of the extracellular domains of CMG2. The vWA domain has been taken from the crystal structure 1tzn, chain ‘a’, and the predicted Ig-like model (this work) has been grafted onto the crystal structure of the vWA domain (1tzn, chain a). To better show the overall fold, the successive secondary structure elements each have a distinct colour from dark-blue (N-terminal) to red (C-terminal). Cysteines participating in predicted disulphide bridges are marked as black spheres.
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fig03: Model of the ectodomain of CMG2Basic representation of the CMG2 protein and its domains, highlighting the positions of the seven cysteines and HFS mutations analysed in this study.Structural model of the extracellular domains of CMG2. The vWA domain has been taken from the crystal structure 1tzn, chain ‘a’, and the predicted Ig-like model (this work) has been grafted onto the crystal structure of the vWA domain (1tzn, chain a). To better show the overall fold, the successive secondary structure elements each have a distinct colour from dark-blue (N-terminal) to red (C-terminal). Cysteines participating in predicted disulphide bridges are marked as black spheres.

Mentions: Our subsequent aim was to understand the mechanisms leading to the premature degradation of CMG2 mutants in patients. Mutation p.C39F found in Patient 1 maps to the stem of the vWA domain (Fig 3). Upon expression of the vWA domain in Escherichia coli, this cysteine forms a disulphide bridge with Cys-218 (Lacy et al, 2004). The two other mutations, p.V310F (Patient 2) and p.C315W (Patient 3) map to the Ig-like domain, the structure of which is unknown. We therefore modelled this domain using a combination of fold recognition (Biegert et al, 2006; Soding, 2005) and manual modelling (Guex & Peitsch, 1997). The model shows an Ig-like fold (Fig 3B) where, quite remarkably, four cysteine residues are positioned in a manner compatible with the formation of two disulphide bridges: C230-C315 and C255-C279. In further support of the model, the two potential N-glycosylation sites, at least one of which is known to be modified (Deuquet et al, 2009), localize to the solvent exposed surface of the domain.


Hyaline fibromatosis syndrome inducing mutations in the ectodomain of anthrax toxin receptor 2 can be rescued by proteasome inhibitors.

Deuquet J, Lausch E, Guex N, Abrami L, Salvi S, Lakkaraju A, Ramirez MC, Martignetti JA, Rokicki D, Bonafe L, Superti-Furga A, van der Goot FG - EMBO Mol Med (2011)

Model of the ectodomain of CMG2Basic representation of the CMG2 protein and its domains, highlighting the positions of the seven cysteines and HFS mutations analysed in this study.Structural model of the extracellular domains of CMG2. The vWA domain has been taken from the crystal structure 1tzn, chain ‘a’, and the predicted Ig-like model (this work) has been grafted onto the crystal structure of the vWA domain (1tzn, chain a). To better show the overall fold, the successive secondary structure elements each have a distinct colour from dark-blue (N-terminal) to red (C-terminal). Cysteines participating in predicted disulphide bridges are marked as black spheres.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3377065&req=5

fig03: Model of the ectodomain of CMG2Basic representation of the CMG2 protein and its domains, highlighting the positions of the seven cysteines and HFS mutations analysed in this study.Structural model of the extracellular domains of CMG2. The vWA domain has been taken from the crystal structure 1tzn, chain ‘a’, and the predicted Ig-like model (this work) has been grafted onto the crystal structure of the vWA domain (1tzn, chain a). To better show the overall fold, the successive secondary structure elements each have a distinct colour from dark-blue (N-terminal) to red (C-terminal). Cysteines participating in predicted disulphide bridges are marked as black spheres.
Mentions: Our subsequent aim was to understand the mechanisms leading to the premature degradation of CMG2 mutants in patients. Mutation p.C39F found in Patient 1 maps to the stem of the vWA domain (Fig 3). Upon expression of the vWA domain in Escherichia coli, this cysteine forms a disulphide bridge with Cys-218 (Lacy et al, 2004). The two other mutations, p.V310F (Patient 2) and p.C315W (Patient 3) map to the Ig-like domain, the structure of which is unknown. We therefore modelled this domain using a combination of fold recognition (Biegert et al, 2006; Soding, 2005) and manual modelling (Guex & Peitsch, 1997). The model shows an Ig-like fold (Fig 3B) where, quite remarkably, four cysteine residues are positioned in a manner compatible with the formation of two disulphide bridges: C230-C315 and C255-C279. In further support of the model, the two potential N-glycosylation sites, at least one of which is known to be modified (Deuquet et al, 2009), localize to the solvent exposed surface of the domain.

Bottom Line: Through the analysis of four patients, we identify three novel mutants and determine their effects at the cellular level.Mutations in the Ig-like domain prevent proper disulphide bond formation and are more efficiently targeted to ER-associated degradation.Finally, we show that mutant CMG2 can be rescued in fibroblasts of some patients by treatment with proteasome inhibitors and that CMG2 is then properly transported to the plasma membrane and signalling competent, identifying the ER folding and degradation pathway components as promising drug targets for HFS.

View Article: PubMed Central - PubMed

Affiliation: Ecole Polytechnique Fédérale de Lausanne, Global Health Institute, Lausanne, Switzerland.

Show MeSH
Related in: MedlinePlus