Publication

The Copper Metabolism MURR1 Domain Protein 1 (COMMD1) Modulates the Aggregation of Misfolded Protein Species in a Client-Specific Manner

Vonk, W. I. M., Kakkar, V., Bartuzi, P., Jaarsma, D., Berger, R., Hofker, M. H., Klomp, L. W. J., Wijmenga, C., Kampinga, H. H. & van de Sluis, B., 1-Apr-2014, In : PLoS ONE. 9, 4, 13 p., e92408.

Research output: Contribution to journalArticleAcademicpeer-review

The Copper Metabolism MURR1 domain protein 1 (COMMD1) is a protein involved in multiple cellular pathways, including copper homeostasis, NF-kappa B and hypoxia signalling. Acting as a scaffold protein, COMMD1 mediates the levels, stability and proteolysis of its substrates (e.g. the copper-transporters ATP7B and ATP7A, RELA and HIF-1 alpha). Recently, we established an interaction between the Cu/Zn superoxide dismutase 1 (SOD1) and COMMD1, resulting in a decreased maturation and activation of SOD1. Mutations in SOD1, associated with the progressive neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS), cause misfolding and aggregation of the mutant SOD1 (mSOD1) protein. Here, we identify COMMD1 as a novel regulator of misfolded protein aggregation as it enhances the formation of mSOD1 aggregates upon binding. Interestingly, COMMD1 co-localizes to the sites of mSOD1 inclusions and forms high molecular weight complexes in the presence of mSOD1. The effect of COMMD1 on protein aggregation is client-specific as, in contrast to mSOD1, COMMD1 decreases the abundance of mutant Parkin inclusions, associated with Parkinson's disease. Aggregation of a polyglutamine-expanded Huntingtin, causative of Huntington's disease, appears unaltered by COMMD1. Altogether, this study offers new research directions to expand our current knowledge on the mechanisms underlying aggregation disease pathologies.

Original languageEnglish
Article numbere92408
Number of pages13
JournalPLoS ONE
Volume9
Issue number4
Publication statusPublished - 1-Apr-2014

    Keywords

  • AMYOTROPHIC-LATERAL-SCLEROSIS, MOTOR-NEURON DISEASE, SUPEROXIDE-DISMUTASE SOD1, EPITHELIAL SODIUM-CHANNEL, MUTANT SOD1, CU,ZN-SUPEROXIDE DISMUTASE, HUNTINGTONS-DISEASE, PARKINSONS-DISEASE, FAMILIAL ALS, IN-VIVO

Download statistics

No data available

ID: 13998817