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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
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DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
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Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
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Pathogenic R163W Variant of the Copper Chaperone for Sod1 (Ccs) Functions as an Anti-chaperone.

Bei Zhang1, Stefanie D Boyd1, Dannie Zhabilov1

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Biochemistry
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A mutation in the copper chaperone for Sod1 (Ccs) causes instability and copper dysregulation, leading to neurodegeneration. This study reveals a novel mechanism of Ccs dysfunction acting as an anti-chaperone.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • The copper chaperone for Sod1 (Ccs) is essential for activating Cu,Zn superoxide dismutase (Sod1).
  • Mutations in Ccs can lead to severe neurological disorders.
  • The R163W Ccs mutation was identified in an infant with fatal neurological abnormalities.

Purpose of the Study:

  • To elucidate the molecular mechanism underlying the R163W Ccs mutation's pathogenic effects.
  • To develop a data-driven model for R163W-related phenotypes.
  • To understand how Ccs dysfunction leads to human pathogenesis.

Main Methods:

  • Comprehensive structural and functional analysis of the R163W Ccs mutant.
  • Biochemical assays to assess protein stability, metal binding, and redox activity.
  • Investigating protein aggregation and Sod1 activation/deactivation.

Main Results:

  • The R163W mutation destabilizes Ccs, leading to zinc deficiency and impaired Sod1 activation.
  • R163W Ccs exhibits novel copper reduction and disulfide bond formation in its Sod1-like domain (D2).
  • This altered copper binding converts R163W Ccs into a copper scavenger (anti-chaperone), accelerating Sod1 deactivation and promoting aggregation.

Conclusions:

  • The R163W Ccs mutation disrupts normal copper and zinc homeostasis.
  • This dysfunction leads to a novel anti-chaperone activity and protein aggregation, explaining pathogenesis.
  • Presents the first molecular mechanism for Ccs-related neurodegenerative disease.