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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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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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Mitochondrial precursors are partially unfolded or loosely folded polypeptide chains. Newly synthesized precursors are inhibited from spontaneously folding into their native conformation by the cytosolic chaperones, heat shock proteins 70 (Hsp70), and mitochondrial import stimulation factors (MSFs). Precursors bound to MSFs are guided to the TOM70-TOM37 receptors, while precursors bound to Hsp70  chaperones are targetted to TOM20-TOM22 receptor complexes.
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Assays for the Degradation of Misfolded Proteins in Cells
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PSMC5 insufficiency and P320R mutation impair proteasome function.

Zhong-Qiu Yu1,2, Jenny Carmichael3, Galen A Collins4,5

  • 1Cambridge Institute for Medical Research, The Keith Peters Building, Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, United Kingdom.

Human Molecular Genetics
|May 22, 2024
PubMed
Summary
This summary is machine-generated.

Mutations in PSMC5, a proteasome subunit, cause neurodevelopmental disorders by impairing proteasome function. This study links PSMC5 variants to these conditions, highlighting proteasome dysfunction as a key pathogenic mechanism.

Keywords:
PSMC5developmental delayneurodevelopmental disorderproteasomeprotein degradation

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Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • The ubiquitin-proteasome system is crucial for protein degradation.
  • Proteasome dysfunction is implicated in neurodegenerative and neurodevelopmental disorders.

Purpose of the Study:

  • To investigate the role of PSMC5 mutations in neurodevelopmental disorders.
  • To understand the functional consequences of PSMC5 insufficiency and specific mutations.

Main Methods:

  • Genetic analysis of individuals with neurodevelopmental disorders.
  • Cellular studies to assess proteasome function and apoptosis.
  • Biochemical assays to examine protein complex interactions.

Main Results:

  • Identified PSMC5 mutations (P320R, R325W, Q160A, Q69 nonsense) in individuals with neurodevelopmental disorders.
  • PSMC5 insufficiency and the P320R mutation impair proteasome function and induce apoptosis.
  • The P320R mutation weakens the 19S regulatory particle and 20S core particle association.

Conclusions:

  • PSMC5 variants are pathogenic causes of neurodevelopmental disorders.
  • Proteasome dysfunction resulting from PSMC5 mutations underlies these conditions.