Within every cell, molecular chaperones work to maintain order. Among the most studied is the Heat shock protein 70 family (Hsp70), found in virtually all living organisms from bacteria to humans. Hsp70 acts as a caretaker for other proteins, ensuring they are correctly shaped and functional, which safeguards the cell’s overall health.
The Primary Role of Protein Folding
For any protein to perform its task, it must first be folded into a precise three-dimensional structure. This process is comparable to complex origami, and Hsp70 functions as a master of this cellular process. It guides newly created proteins into their correct final forms, preventing them from misfolding or clumping together with other proteins.
This process is powered by adenosine triphosphate (ATP). The Hsp70 machinery operates in a cycle of binding and release that is regulated by ATP and helper proteins called co-chaperones. When Hsp70 binds to a protein, it holds it securely, and the subsequent use of ATP causes Hsp70 to change shape, releasing the protein to give it a fresh opportunity to fold correctly.
Hsp70 also acts as a quality control mechanic, inspecting existing proteins that may have lost their shape. By identifying and helping to refold these malformed proteins, Hsp70 prevents the accumulation of non-functional and potentially harmful protein aggregates. This maintenance ensures the cell’s protein machinery runs smoothly.
Responding to Cellular Stress
While Hsp70 performs its duties under normal conditions, its production increases dramatically when the cell faces stress. Cellular stress can arise from sources like high temperatures—how “heat shock” proteins got their name—toxins, radiation, or a lack of oxygen. These conditions can cause proteins to lose their shape, or denature, on a massive scale.
In response, the cell activates the heat shock response. A sensor protein, Heat Shock Factor 1 (HSF1), detects the presence of damaged proteins. Under normal conditions, Hsp70 binds to HSF1, keeping it inactive. When stress causes an abundance of damaged proteins, Hsp70 is pulled away to deal with them, releasing HSF1.
Once freed, HSF1 moves into the cell’s nucleus, where it binds to DNA and initiates a massive increase in the production of Hsp70. This surge of Hsp70 acts as an emergency response team, managing the widespread damaged proteins to prevent them from forming toxic clumps. This rapid response helps protect the cell’s components, allowing it to survive conditions that would otherwise be fatal.
Managing Protein Transport and Removal
Hsp70 is also involved in managing the lifecycle of proteins, including their transport to different cellular compartments and their eventual disposal. Many proteins must be moved across membranes to reach destinations like the mitochondria or the endoplasmic reticulum. Hsp70 keeps these proteins in a partially unfolded, “transport-ready” state so they can pass through the narrow channels of these membranes.
Inside specific organelles, specialized versions of Hsp70 continue the job. For instance, a variant within the endoplasmic reticulum helps newly arrived proteins fold correctly in their new environment. This ensures that proteins destined for secretion or for embedding in the cell’s membranes are properly assembled.
Hsp70 also plays a part in the cell’s waste management system. When a protein is too damaged to be repaired, it must be removed. Hsp70, in partnership with other co-chaperones, identifies these terminally misfolded proteins. The system then attaches a molecular tag called ubiquitin to the damaged protein, marking it for destruction by the proteasome.
Involvement in Disease Processes
The functions of Hsp70 in protein quality control have significant implications for human health, particularly in cancer and neurodegenerative diseases.
Cancer
Cancer cells, which grow and divide rapidly, operate under constant internal stress and produce large amounts of abnormal proteins. To survive these conditions, they hijack the cell’s protective mechanisms, leading to abnormally high levels of Hsp70. This abundance of Hsp70 helps tumor cells withstand chemotherapy and radiation, making them resistant to treatment. The reliance of cancer cells on Hsp70 has made it a target for new anti-cancer therapies.
Neurodegenerative Diseases
In neurodegenerative disorders like Alzheimer’s and Parkinson’s disease, the problem is the misfolding and aggregation of specific proteins. In Alzheimer’s, proteins called amyloid-beta and tau form toxic plaques and tangles. In Parkinson’s, a protein named alpha-synuclein clumps together, leading to the death of neurons. Hsp70 can counteract this by binding to these aggregation-prone proteins, preventing them from forming harmful clusters.
Evidence suggests that boosting the levels or activity of Hsp70 could be a protective strategy against these diseases. Studies in animal models have shown that increasing Hsp70 can reduce the accumulation of toxic protein aggregates. This has opened a promising avenue of research focused on enhancing the Hsp70 system in the brain.