What Are the Reasons for the Production of Misfolded Proteins?
Creators: name: Hussain, Zahid
Publisher: name: Zenodo
Year: 2025
Subjects: What
Reasons
Production
Misfolded Proteins?

description: What Are the Reasons for the Production of Misfolded Proteins?

Abstract

Protein misfolding is a critical issue in cellular biology, often leading to severe consequences, including the development of various diseases such as Alzheimer's, Parkinson's, and Huntington's. Understanding the underlying causes of protein misfolding is essential to addressing its impact on human health and biotechnology. This review article explores the multifaceted reasons for the production of misfolded proteins, encompassing genetic mutations, environmental stressors, post-translational modifications, and cellular machinery malfunctions. By integrating insights from recent research, this review aims to highlight the complexities of protein folding, the consequences of misfolding, and potential strategies to mitigate these errors.




Introduction

Proteins are fundamental macromolecules responsible for most cellular functions. Their proper function relies on precise folding into specific three-dimensional structures. However, proteins can sometimes fail to fold correctly, resulting in misfolded conformations. Misfolded proteins are implicated in numerous diseases and can also pose challenges in industrial and therapeutic protein production (Dobson, 2003).

Understanding why proteins misfold involves examining the intricate processes of protein biosynthesis, folding, and quality control. This article delves into the primary causes of protein misfolding, offering a comprehensive review of contributing factors and their implications.




Overview of Protein Folding

Protein folding begins as nascent polypeptides emerge from ribosomes during translation. This process is guided by the protein’s amino acid sequence (Anfinsen, 1973). Folding can be facilitated by molecular chaperones and requires a finely tuned cellular environment. However, numerous factors can disrupt this process, leading to misfolded proteins.

Key Players in Protein Folding



Molecular Chaperones: Proteins such as Hsp70 and Hsp90 assist in folding and prevent aggregation.

Proteostasis Networks: Systems such as the ubiquitin-proteasome pathway ensure proper folding and degrade misfolded proteins.

Post-Translational Modifications (PTMs): PTMs like glycosylation and phosphorylation can influence folding outcomes (Hartl et al., 2011).





Genetic Causes of Misfolded Proteins

Mutations in Protein Coding Genes

Genetic mutations can alter the amino acid sequence, disrupting the intrinsic folding properties of proteins. For example:



Cystic Fibrosis: A deletion in the CFTR gene (F508del) leads to protein misfolding and degradation (Cheng et al., 1990).

Sickle Cell Anemia: A single point mutation in the HBB gene alters hemoglobin structure, causing aggregation (Perutz, 1978).


Trinucleotide Repeat Expansions

Certain diseases, such as Huntington's, involve expansions of specific trinucleotide repeats, producing proteins prone to aggregation (Ross & Tabrizi, 2011).

Polymorphisms in Chaperone Genes

Variations in chaperone genes can reduce the efficiency of folding machinery, increasing the likelihood of misfolding (Hartl et al., 2011).




Environmental Stressors

Heat Shock

Elevated temperatures destabilize protein structures, leading to aggregation. Heat shock proteins (HSPs) often fail to cope with excessive misfolding under prolonged stress (Lindquist & Craig, 1988).

Oxidative Stress

Reactive oxygen species (ROS) can oxidize amino acid side chains, disrupting protein structure and function. This is particularly relevant in aging and neurodegenerative diseases (Halliwell, 2006).

pH Imbalances

Abnormal pH levels can alter charge distributions, impacting folding. For example, acidosis can induce misfolding in metabolic enzymes (Dobson, 2003).

Chemical Exposure

Certain chemicals, such as heavy metals and organic solvents, can denature proteins, leading to misfolding and aggregation (Uversky et al., 2001).




Cellular Machinery Malfunctions

Ribosomal Errors

Errors during translation can introduce incorrect amino acids, disrupting the folding process. These errors are more common under stress conditions, such as nutrient deprivation (Zhang et al., 2019).

Impaired Quality Control Systems

Defects in proteostasis networks, including chaperones and degradation pathways, contribute to misfolding. For instance:



Proteasome Dysfunction: Leads to accumulation of misfolded proteins (Ciechanover & Kwon, 2015).

Autophagy Deficiency: Reduces clearance of aggregated proteins, exacerbating cellular toxicity (Menzies et al., 2015).





Role of Post-Translational Modifications

Glycosylation Errors

Glycosylation is critical for proper folding, particularly for secreted and membrane proteins. Defects in glycosylation pathways can lead to diseases such as congenital disorders of glycosylation (Jaeken, 2011).

Aberrant Phosphorylation

Hyperphosphorylation of tau protein is a hallmark of Alzheimer’s disease, contributing to misfolding and aggregation (Wang & Mandelkow, 2016).

Disulfide Bond Formation

Errors in disulfide bond formation can result in misfolded proteins. This is especially relevant in the endoplasmic reticulum (ER), where many secretory proteins are folded (Tu & Weissman, 2004).




Consequences of Misfolded Proteins

Loss of Function

Misfolded proteins often lose their intended function, leading to cellular dysfunction. For example, misfolded CFTR protein fails to regulate chloride channels in cystic fibrosis (Cheng et al., 1990).

Gain of Toxic Function

In some cases, misfolded proteins acquire toxic properties, such as the ability to aggregate and disrupt cellular processes. This is a hallmark of prion diseases (Prusiner, 1998).

Cellular Stress

Accumulation of misfolded proteins triggers ER stress and the unfolded protein response (UPR), which can lead to apoptosis if unresolved (Walter & Ron, 2011).




Strategies to Prevent or Mitigate Misfolding

Enhancing Proteostasis



Chaperone Modulators: Small molecules that enhance chaperone activity are being explored as potential therapies (Calamini et al., 2012).

Proteasome Activators: Compounds that boost proteasome activity may help clear misfolded proteins (Ciechanover & Kwon, 2015).


Gene Therapy

Correcting genetic mutations through CRISPR-Cas9 or other gene-editing tools holds promise for diseases caused by misfolded proteins (Doudna & Charpentier, 2014).

Reducing Environmental Stress

Lifestyle changes and antioxidant therapies can mitigate oxidative stress and reduce the risk of protein misfolding (Halliwell, 2006).

Modulating PTMs

Targeting aberrant PTMs, such as hyperphosphorylation, with specific inhibitors is an active area of research (Wang & Mandelkow, 2016).




Future Directions

Advanced Imaging Techniques

Cryo-electron microscopy (cryo-EM) and super-resolution microscopy are enabling detailed studies of misfolded protein structures (Cheng, 2018).

Systems Biology Approaches

Integrating multi-omics data can provide a holistic view of the pathways involved in protein misfolding and aggregation (Aebersold & Mann, 2016).

Synthetic Biology

Engineering synthetic chaperones or proteostasis networks could offer novel solutions for managing protein misfolding (Silver, 2019).




Conclusion

The production of misfolded proteins arises from a combination of genetic, environmental, and cellular factors. Understanding these causes is crucial for developing effective therapeutic strategies. Advances in molecular biology, systems biology, and synthetic biology hold promise for addressing the challenges posed by protein misfolding, paving the way for innovative treatments for associated diseases.




 

 

 

 

References



Anfinsen, C. B. (1973). Principles that govern the folding of protein chains. Science, 181(4096), 223-230. https://doi.org/10.1126/science.181.4096.223

Dobson, C. M. (2003). Protein folding and misfolding. Nature, 426(6968), 884-890. https://doi.org/10.1038/nature02261

Hartl, F. U., Bracher, A., & Hayer-Hartl, M. (2011). Molecular chaperones in protein folding and proteostasis. Nature, 475(7356), 324-332. https://doi.org/10.1038/nature10317

Prusiner, S. B. (1998). Prions. Proceedings of the National Academy of Sciences, 95(23), 13363-13383. https://doi.org/10.1073/pnas.95.23.13363

Wang, Y., & Mandelkow, E. (2016). Tau in physiology and pathology. Nature Reviews Neuroscience, 17(1), 22-35. https://doi.org/10.1038/nrn.2015.1

Halliwell, B. (2006). Oxidative stress and neurodegeneration: where are we now? Journal of Neurochemistry, 97(6), 1634-1658. https://doi.org/10.1111/j.1471-4159.2006.03907.x