New Study on Protein Folding and Chaperones Offers Insights into Neurodegenerative Diseases

Proteins, which are involved in nearly every cellular process, must adopt a well-defined 3-D structure, known as the ‘native conformation,’ to function correctly.

A groundbreaking new method to study protein folding and the role of associated chaperones, which protect proteins from non-native interactions, promises to deepen our understanding of what triggers protein folding. This insight could significantly impact the tracking and progression of diseases such as cancer, Parkinson’s, and Alzheimer’s.

Proteins, which are involved in nearly every cellular process, must adopt a well-defined 3-D structure, known as the ‘native conformation,’ to function correctly. However, various chemical, environmental, or physical stress conditions can cause proteins to misfold or unfold, leading to dysfunction. This misfolding can result in the aggregation of toxic materials within cells, contributing to diseases like Alzheimer’s and Parkinson’s.

While some newly translated proteins fold spontaneously, many require the assistance of molecular chaperones to achieve their native state and avoid non-native interactions. These chaperones are crucial for maintaining protein functionality, aiding in folding, and repairing unfolding or misfolding.

Given their importance, researchers have long studied the structure and function of molecular chaperones within cells. Traditional bulk biochemical measurements have provided valuable insights into protein folding efficiency and the prevention of aggregation when chaperones are involved. However, these methods fall short in exploring the heterogeneity of chaperone molecules and their function in diverse cells. They also miss the significance of transient states in metabolic processes.

Recent advancements in single-molecule techniques have opened new avenues for exploring the fundamental properties of biomolecules involved in biochemical reactions. A team at the S.N. Bose National Centre for Basic Sciences, led by Prof. Shubhasis Halder, has developed a Covalent Magnetic Tweezer (CMT) to study the physical and chemical properties of protein molecules and the action of chaperones on protein folding and function.

This innovative approach has provided unprecedented insights into the dynamics of chaperone-assisted protein folding. Key players in this molecular process are the heat shock proteins Hsp70 and Hsp90, two of the most studied molecular chaperones.

Single-molecule force spectroscopy has revealed the complex dynamics of Hsp70-induced protein manipulation. Understanding these details is crucial for comprehending how Hsp70 aids in protein folding, stabilization, and transport under various cellular conditions.

Similarly, Hsp90 is known to activate and stabilize numerous proteins, including steroid hormone receptors and signaling kinases. Single-molecule techniques have been used to characterize the multiple pathways and states of the Hsp90 complex. This research has unveiled the multifaceted capabilities of magnetic tweezers in manipulating protein structures.

The findings have revealed novel mechanisms of molecular chaperones and provided insights into their function and implications for protein homeostasis and human diseases. A review of these studies was published in the journal Trends in Biochem Sciences.

The review highlights the mechanical dynamics underlying chaperone interactions with substrates under force. It also explains how chaperones, especially those within cellular tunnels, utilize the mechanical energy from the tunnel to guide the folding process, ensuring the proper maturation of proteins essential for cellular functions. The investigation further explores the diverse mechanical functions exhibited by chaperones under force.

Researchers are beginning to understand the mechanisms by which Alzheimer’s disease sets in due to brain stiffness. Understanding the physical basis of degenerative diseases like Alzheimer’s and Parkinson’s at a molecular level will enable the design of drugs targeting the mechanical roles of chaperones, potentially preventing the progression of these diseases.

“However, a lot remains unanswered as we work at the junction of basic and translational research,” says Debojyoti Chowdhury, co-author of the review paper.

As gaps in understanding the dynamics of chaperones and their client proteins are bridged, pharmaceutical science will be poised for significant advancements. Single-molecule techniques hold the key to this revolution.