Indian Scientists Discover p47 Protein’s Hidden Role as a Mechanical Chaperone

The protein, p47, long regarded merely as a helper molecule, has been revealed to play a direct role in protecting other proteins from mechanical stress inside living cells.

In a groundbreaking study, researchers at the S. N. Bose National Centre for Basic Sciences (SNBNCBS), Kolkata, have uncovered a surprising new function for a little-known protein that could reshape our understanding of cellular resilience. The protein, p47, long regarded merely as a helper molecule, has been revealed to play a direct role in protecting other proteins from mechanical stress inside living cells.

The discovery provides new insights into how cells withstand constant physical forces and could pave the way for novel therapies targeting conditions such as cardiomyopathies (heart muscle disease) and laminopathies (genetic disorders involving fragile structural proteins).

The Mechanical Challenge Inside Cells

Life inside a cell is far from static. Proteins — the workhorses of biology — are continuously pushed, pulled, and twisted during critical activities such as transport, degradation, and remodeling of the cell’s internal skeleton. These mechanical forces often cause proteins to unfold or lose stability, jeopardizing their function.

Traditionally, chaperone proteins have been credited with maintaining order by ensuring correct folding and stability. However, the role of accessory cofactors — proteins that assist larger molecular machines — in directly protecting proteins under force has been less understood.

p47 Steps Out of the Shadows

The team led by Dr. Shubhasis Haldar at SNBNCBS turned their attention to p47, a cofactor of the powerful molecular machine p97. While p97 is central to moving and degrading proteins, p47 was largely seen as its assistant, involved in processes such as protein trafficking and membrane fusion.

Using single-molecule magnetic tweezers, the researchers applied finely controlled pulling forces to proteins in real time, simulating the stresses encountered during transport across membranes or within the crowded cell interior.

To their surprise, they discovered that p47 is not just a bystander. It acted as a “mechanical chaperone”, binding to stretched proteins and enabling them to refold even under constant pulling forces. This unexpected ability mirrors the protective role of canonical chaperones but comes from an accessory factor once thought to be passive.

How p47 Protects Proteins

The experiments revealed that p47 can enhance the mechanical efficiency of protein extraction from the endoplasmic reticulum (ER) lumen into the cytoplasm. By stabilizing polypeptides under stress and guiding them through narrow pores, p47 reduces the risk of misfolding and improves the success of protein translocation.

This finding represents the first direct, single-molecule evidence that cofactors like p47 possess autonomous, force-dependent chaperone-like activity.

Implications for Medicine and Biotechnology

The discovery carries significant implications for therapeutic strategies. Many diseases arise when proteins fail to remain stable under physical stress, including:

• Heart muscle diseases, where mechanical strain damages structural proteins.

• Laminopathies, genetic disorders affecting nuclear proteins that are prone to mechanical breakdown.

• Neurodegenerative diseases, where protein misfolding and aggregation are key features.

By targeting or engineering cofactors such as p47, scientists may develop new approaches to stabilizing vulnerable proteins in disease contexts. The findings also expand the functional repertoire of accessory proteins, suggesting that many helpers once dismissed as minor players may harbor hidden protective roles.

A Landmark Study from India

The research, published in Biochemistry as part of a special issue celebrating the 25th Anniversary of the Chemical Research Society of India (CRSI), marks a milestone in Indian contributions to molecular biophysics. It highlights how innovative single-molecule techniques can illuminate previously unseen aspects of cellular machinery.

Speaking on the significance, Dr. Haldar noted that this discovery challenges long-held assumptions:

“Our work shows that proteins once considered mere assistants can themselves act as guardians of stability under force. This opens up an entirely new dimension in understanding cellular mechanics.”

Looking Forward

As the field of mechanobiology advances, the SNBNCBS findings underscore the importance of revisiting the roles of accessory proteins. Future research could explore whether other cofactors possess similar mechanical chaperone activities and how these can be harnessed for biomedical innovation.

By shining light on p47’s hidden strength, the study not only deepens our understanding of protein quality control but also points toward new therapeutic frontiers for diseases of mechanical fragility.