response to misfolded protein

Definition

Target type: biologicalprocess

Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a misfolded protein stimulus. [GOC:go_curators]

Response to misfolded protein is a complex cellular process that aims to restore protein homeostasis (proteostasis) and prevent the accumulation of misfolded or aggregated proteins, which can be toxic and lead to cellular dysfunction and disease. This response involves a coordinated interplay of several molecular mechanisms, including:

1. **Protein chaperones:** These molecules assist in the proper folding of newly synthesized proteins and can also refold misfolded proteins back to their native state. Examples include heat shock proteins (HSPs), such as HSP70 and HSP90, and chaperonins, such as GroEL/ES.
2. **Protein degradation systems:** Misfolded proteins that cannot be refolded are targeted for degradation. This occurs through two major pathways:
- **Ubiquitin-proteasome system (UPS):** Misfolded proteins are tagged with ubiquitin chains, marking them for degradation by the proteasome, a large protein complex.
- **Autophagy:** Damaged organelles and misfolded proteins are sequestered into double-membrane vesicles called autophagosomes, which then fuse with lysosomes for degradation.
3. **Molecular chaperone networks:** These networks include specific chaperones that recognize and bind to misfolded proteins, facilitating their refolding or targeting them for degradation. Chaperone networks can be further divided based on their function, including:
- **Folding chaperones:** Assist in the proper folding of nascent proteins.
- **Holdase chaperones:** Bind to misfolded proteins and prevent aggregation.
- **Disaggregation chaperones:** Extract misfolded proteins from aggregates.
4. **Stress response pathways:** Cellular stress caused by misfolded proteins triggers various signaling pathways that activate the expression of chaperones, proteasomal components, and other proteins involved in the response. These pathways include the unfolded protein response (UPR) and the heat shock response (HSR).
5. **Quality control mechanisms:** These mechanisms ensure that newly synthesized proteins are properly folded before they reach their functional destination. This includes:
- **Ribosome-associated quality control (RQC):** Newly synthesized proteins that fail to fold properly are targeted for degradation by the ribosome.
- **ER quality control (ERQC):** Proteins that misfold in the endoplasmic reticulum (ER) are subjected to a series of quality control checkpoints before being released from the ER.

The response to misfolded protein is essential for maintaining cellular health and function. Defects in these mechanisms can contribute to the development of a variety of diseases, including neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease), cancer, and metabolic diseases.'
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Proteins (2)

Compounds (188)