Molecular chaperone

Molecular chaperones are a class of proteins that play a critical role in the folding, assembly, and stabilization of other proteins. Their primary function is to assist proteins in reaching their proper three-dimensional structure, which is essential for their biological activity. Molecular chaperones are involved in various cellular processes, including protein synthesis, translocation across membranes, and the response to stress conditions that can lead to protein misfolding and aggregation.

Function

Molecular chaperones do not form part of the final structure of the protein they assist. Instead, they transiently interact with their substrates, preventing improper interactions that could lead to nonfunctional structures or aggregates. This process is crucial for maintaining cellular homeostasis and preventing diseases associated with protein misfolding, such as Alzheimer's disease, Parkinson's disease, and cystic fibrosis.

There are several families of molecular chaperones, including the heat shock proteins (HSPs), chaperonins, and Hsp90 family. Each family has distinct mechanisms of action but generally operates by recognizing and binding to exposed hydrophobic regions on the substrate protein, thereby stabilizing it and facilitating correct folding.

Types

Heat Shock Proteins (HSPs)

HSPs are among the most studied molecular chaperones. They are upregulated in response to stress, such as increased temperatures, which can cause proteins to unfold. HSPs help refold these proteins and prevent aggregation. Examples include Hsp70, which assists in the early stages of protein folding, and Hsp60, which forms a complex known as a chaperonin that provides a protected environment for protein folding.

Chaperonins

Chaperonins are large, complex proteins that provide an isolated environment for protein folding. The most well-known chaperonins are the GroEL/GroES complex in bacteria and the TRiC/CCT complex in eukaryotes. These complexes have a barrel-like structure where protein folding occurs away from the crowded cellular environment.

Hsp90

Hsp90 is another important molecular chaperone that assists in the final stages of protein folding. It is involved in the maturation of a wide range of protein substrates, including kinases and hormone receptors. Hsp90 function is particularly crucial for the stability and activity of many signaling proteins.

Role in Disease

Improper function of molecular chaperones can lead to the accumulation of misfolded proteins, which is a hallmark of several neurodegenerative diseases. For example, in Alzheimer's disease, the accumulation of misfolded amyloid-beta peptides leads to the formation of amyloid plaques. Molecular chaperones are also involved in cancer, as they can stabilize mutated proteins that promote cancer cell growth and survival.

Therapeutic Potential

Given their role in protein folding and stabilization, molecular chaperones are considered potential therapeutic targets for diseases caused by protein misfolding. Small molecule inhibitors of Hsp90, for example, are being explored as cancer therapies because they can destabilize oncogenic proteins. Similarly, enhancing the activity of certain chaperones might help in the treatment of neurodegenerative diseases by reducing the accumulation of misfolded proteins.

See Also

• Protein folding
• Proteostasis
• Unfolded protein response