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The role of COMMD1 in membrane protein quality control


Project Description

Misfolded proteins represent a continuous threat to cell viability, which if allowed to accumulate, can disrupt cellular function and induce cell death. Therefore, cells possess quality control systems in order to identify and eliminate these aberrant polypeptides. A large number of human diseases are linked to protein misfolding, and therefore there is great interest in defining the components that make up the cell’s protein quality control systems. Copper metabolism gene MURR1 domain-containing protein (COMMD1) is the founding member of a family of 10 widely expressed small proteins containing a conserved COMM domain. COMMD1 was first identified due to its association with copper toxosis in dogs and humans, and has since been implicated in a range of cellular processes including NF-kB and HIF-1 signalling and ion transport pathways. Although the mechanism of COMMD1 action in these processes is unknown, a common feature its ability to modulate the ubiquitination and stability of its targets. COMMD1 interacts with and enhances the activity of several ubiquitin ligases, and hence it has been proposed that COMMD proteins could act as scaffolds that bring ubiquitin ligases together with their substrate proteins. Notably, COMMD1 promotes ubiquitination of a number of integral membrane proteins, including the copper transporters ATP7A and B, cystic fibrosis transmembrane conductance regulator (CFTR), the Na-K-2Cl cotransporter, and subunits of the epithelial sodium channel (ENaC). Although it is well established that ubiquitination regulates the stability and trafficking of membrane proteins, the wider role of COMMD1 in membrane protein quality control has not yet been investigated. The aim of this project is to examine the role of COMMD1 in regulating the biosynthesis, trafficking and degradation of integral membrane proteins.

Techniques: a range of molecular biology, bioimaging, biochemistry, cell biology and proteomics approaches will be utilised.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.


References

Drévillon et al. (2011) COMMD1-mediated ubiquitination regulates CFTR trafficking. PLoS One 6, e18334

Fedoseienko et al. (2014) Functional understanding of the versatile protein copper metabolism MURR1 domain 1 (COMMD1) in copper homeostasis. Ann N Y Acad Sci.1314, 6-14

Ke et al. (2010) COMMD1 downregulates the epithelial sodium channel through Nedd4-2. Am J Physiol Renal Physiol 298, F1445-1456

Mao et al. (2011) COMMD1 (copper metabolism MURR1 domain-containing protein 1) regulates Cullin RING ligases by preventing CAND1 (Cullin-associated Nedd8-dissociated protein 1) binding. J Biol Chem 286, 32355-32365

Materia et al. (2012) Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. J Biol Chem 287, 2485-2499

Vonk et al. (2014) The Copper Metabolism MURR1 Domain Protein 1 (COMMD1) Modulates the Aggregation of Misfolded Protein Species in a Client-Specific Manner. PLoS One 9, e92408

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