Meet Your Heat Shock Proteins

An Introduction

Like many milestone discoveries, heat shock proteins (HSPs) were discovered by accident. In 1962, the Italian scientist Ferruccio Ritossa was studying fruit fly genetics, when one morning he found his incubator to be set at a temperature higher than normal. Ritossa amusingly denied responsibility for the mistake, even in his write-up of his finding.  He says "I do not remember whether it was John Pulitzer or Inge or Clara Ghini and Giordano who shifted the temperature of my incubator, but one day I noticed a different puffing pattern!"[1] A “puffing pattern” is seen under a microscope when a gene is being transcribed. Those genes were transcribing heat shock proteins, although it would be years before we would know that, and decades before we would know the real significance of that discovery. In fact, we are still discovering the full significance of his discovery. 

Proteins 101

Before we dive in, let’s make sure we are on the same page, with a brief recap on proteins.  What exactly are proteins? Like, a side of chicken? Smaller. We are diving into the cells of that chicken—the microscopic cells that make up every tissue and organ in your body.
Our cells are crowded places. They are not the clean, spacious line drawing from your high school biology textbook, with a nucleus and mitochondrion separated by a white page, substrates moseying over in a leisurely backstroke.  Each of our cells can contain billions of proteins, doing thousands of different jobs.  That line drawing was a bit simplified, of course.  Our cells are astoundingly busy and complex micro-verses.  

Protein Folding 

There are thousands of different proteins- well over 10,000 are identified, and that number increases quickly. By different proteins, I mean different genes encoding proteins with different structures. Proteins are all made of the same 20 amino acids, in long chains of differing sequences, which then fold in into a secondary and tertiary, and sometimes a quaternary structure. [2] Just as the 26 letters in our alphabet form words and then sentences and then a nearly endless number of phrases, the 20 amino acids can form enormous numbers of different protein shapes. And, like the placement of letters and words determines meaning, so does the shape of the protein determine its function.  The enzyme must be the right shape to hold two substrates together, channels must allow a precise number of molecules to pass based on a signal, and a receptor must match its ligand exactly.  The act of proteins folding into their precise shape, and maintaining that shape, is big business in the cell, and a significant amount of the cell's resources are allocated to making sure this goes right. [3]

Housekeeping Proteins

 There are thousands of known different proteins, but only about 10% of these make up most of the proteins in our cells, under normal conditions (about 70% of the proteins in the cell)[2]. These are the regulars, sometimes called the “housekeeping proteins” because they maintain the essential functions of day to day life (metabolism, growth, movement, communication). They are the essential workers.   Heat shock proteins are key essential workers.  One could even argue they are the most essential workers.  They are one of our most abundant proteins, up to 10% of the proteins in a typical cell under normal conditions [4] (so, 10% of that 70%, or 1/7th of the essential workers).  They are also one of or the most conserved families of proteins, meaning they are in all life forms, from prokaryotic bacteria to humans, and they are very similar in all species, having changed very little since the beginning of life.  So, they must be pretty important…

Heat Shock Proteins: Guardians of Protein Shape.

Chaperones and Heat Shock Proteins

We are not quite done with protein folding. Remember the genetic code is translated into a chain of amino acids.  The chain then folds back on itself in its secondary structure, and then again into a tertiary structure, resulting in a unique and precise shape. Of note, some amino acids are hydrophobic, and prefer to be on the inside of the protein (think oily or sticky), and some are hydrophilic, and tend to be on the surface of the folded protein. Folding is such an important function that the cell has a huge family of proteins that is responsible for overseeing the process.  These are called chaperone proteins, or  molecular chaperones.Chaperone proteins and heat shock proteins were being discovered independently in the 1970s, and it was not recognized until the 1980s that there was a large overlap in the two families].  The names stuck though, which often causes confusion even today, decades later. They are sometimes used interchangeably, however technically this is not correct, as only about one fifth of chaperone proteins are activated by heat. [5]

Unfolding and Misfolding

While it is true that the shape of a protein must be precisely accurate, it also cannot be too rigid or unyielding. Many proteins must change their shape to function. Enzymes bind their substrates and catalyze a reaction and then release the product, channels open and close, myosin and actin contract and relax muscles. The protein must be flexible enough to move and function, even to change shape a little, but not so flexible that it falls apart under stress. There is a “just right” level of fluidity or flexibility.  
Yes, proteins can fall apart under stress. Heat stress is a type of stress. Protein “stress” is any factor that causes proteins to increasingly lose their shape and function, and conditions under which the cell struggles to maintain homeostasis.  This could be changes in temperature or pH, low glucose or oxygen, toxic chemicals or heavy metals, radiation, and oxidative stress (oxidative stress is now understood to perhaps be more accurately stated to be the stress rather than just one of the causes of it.)
One final thing about protein unfolding: when a protein unfolds, those “sticky” amino acids that were happily tucked away into the middle of the cell, can become exposed. When multiple proteins unfold, and start floating around bumping into each other, they can stick together via these sticky spots. If this is not controlled, they continue to form large aggregates, which are toxic to the cell. [6]

Toxic Protein Aggregates

Remember how crowded a cell can be? Imagine the cell is a busy airport. Everyone is focused on their task at hand. People swerve around and squeeze past each other, not paying much attention, just focused on where they want to go. Carts go whizzing by with the shrill beep of the horn telling pedestrians to make way. Occasionally they get slowed up a little, but normally the system functions. Now, imagine a cart loses a wheel. The axle drops, and the cart stops short. Now another cart comes along, and bumps the broken cart, and gets a flat tire, and a pole gets bent and sticks out to the side. The pole now hooks the next cart coming through, and so on and so on until there is a huge barricade of broken carts and nothing can get through. Now people start missing their flights, and the pilots can’t get past, and eventually, if not cleared, the whole airport comes to a halt.

Heat Shock Proteins: a crucial cellular defense mechanism

Heat shock proteins are the cart mechanics. They constantly survey the airport for cart breakdowns, and rush over to help as soon as they see a problem.  The goal is to fix the problem and get the cart moving again, which if caught early, is often what happens. If they can’t fix it, they at least will get it out of the way, so it doesn't cause a pile up.  And under typical conditions, they are able to do one of these things, and the airport/ cell keeps running smoothly. 

References

1. De Maio A, Santoro MG, Tanguay RM, Hightower LE. Ferruccio Ritossa’s scientific legacy 50 years after his discovery of the heat shock response: a new view of biology, a new society, and a new journal. Cell Stress Chaperones. 2012;17(2):139-143. doi:10.1007/s12192-012-0320-z 

2. Finka A, Goloubinoff P. Proteomic data from human cell cultures refine mechanisms of chaperone-mediated protein homeostasis. Cell Stress Chaperones. 2013;18(5):591-605. doi:10.1007/s12192-013-0413-3 

3. Kuzu OF, Granerud LJT, Saatcioglu F. Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations. Signal Transduct Target Ther. 2025;10:358. doi:10.1038/s41392-025-02439-w 

4. Hu C, Yang J, Qi Z, et al. Heat shock proteins: Biological functions, pathological roles, and therapeutic opportunities. MedComm. 2022;3(3):e161. doi:10.1002/mco2.161 

5. Richter K, Haslbeck M, Buchner J. The Heat Shock Response: Life on the Verge of Death. Mol Cell. 2010;40(2):253-266. doi:10.1016/j.molcel.2010.10.006 

6. Early steps of protein disaggregation by Hsp70 chaperone and class B J-domain proteins are shaped by Hsp110 - PMC. Accessed September 3, 2026. https://pmc.ncbi.nlm.nih.gov/articles/PMC11479587/