title: The Copper Metabolism MURR1 domain protein 1 (COMMD1) modulates the aggregation of misfolded protein species in a client-specific manner.
abstract: The Copper Metabolism MURR1 domain protein 1 (COMMD1) is a protein involved in multiple cellular pathways, including copper homeostasis, NF-κB 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-1α). 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.
authors.affiliation: University Medical Center Utrecht, Department of Metabolic and Endocrine Diseases, and Netherlands Metabolomics Center, Utrecht, the Netherlands; University Medical Center Utrecht, Complex Genetics Section, Utrecht, the Netherlands.
authors.forename: Willianne I M
authors.initials: WI
authors.lastname: Vonk
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, the Netherlands.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Kakkar
authors.affiliation: University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, the Netherlands.
authors.forename: Paulina
authors.initials: P
authors.lastname: Bartuzi
authors.affiliation: Erasmus Medical Center, Department of Neuroscience, Rotterdam, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Jaarsma
authors.affiliation: University Medical Center Utrecht, Department of Metabolic and Endocrine Diseases, and Netherlands Metabolomics Center, Utrecht, the Netherlands.
authors.forename: Ruud
authors.initials: R
authors.lastname: Berger
authors.affiliation: University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, the Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: University Medical Center Utrecht, Department of Metabolic and Endocrine Diseases, and Netherlands Metabolomics Center, Utrecht, the Netherlands.
authors.forename: Leo W J
authors.initials: LW
authors.lastname: Klomp
authors.affiliation: University Medical Center Utrecht, Complex Genetics Section, Utrecht, the Netherlands; University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Cell Biology, Groningen, the Netherlands.
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.affiliation: University of Groningen, University Medical Center Groningen, Molecular Genetics, Groningen, the Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: van de Sluis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008970:Molecular Weight; D050505:Mutant Proteins / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D066329:Protein Aggregates; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C480519:COMMD1 protein, human; D050505:Mutant Proteins; D010455:Peptides; D066329:Protein Aggregates; C000606290:SOD1 protein, human; C097188:polyglutamine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein