Christian Kaiser appointed Professor of Biophysical Chemistry of Membranes and Proteins

New research aims to unlock how biological proteins fold and become functional

Utrecht University has appointed Christian Kaiser as professor of Biophysical Chemistry of Membranes and Proteins. Kaiser and his team will explore the way biological proteins are produced, processed and transported in the cell. Fundamental insights into these mechanisms could pave the way for new approaches to combat protein-related diseases, such as dementia and cystic fibrosis.

Christian Kaiser and his research team
Prof. Christian Kaiser (pictured third from left) and his research team at Utrecht University.

Proteins are fundamental building blocks of life, and play a crucial role in constructing and maintaining organisms. But the central role that proteins play also has a downside. If proteins are incorrectly produced, processed, or transported, it can lead to very serious conditions, such as dementia and other neurodegenerative diseases.

Yet, our knowledge of how proteins acquire their shape and function is surprisingly incomplete. From his new position at Utrecht University, Prof. Christian Kaiser aims to fill this gap and catalyze new avenues of research into the chemistry and dynamics of proteins.

Form for function

“High school biology textbooks teach us about how proteins are made, through DNA, RNA and molecular machines called ribosomes”, says Kaiser. “But this is not the whole story. In order to become functional, most proteins must adopt a specific three dimensional shape or structure.”

What actually happens when cells transport proteins through their membranes is largely unclear

Moreover, proteins are often not produced at the location where they are ultimately needed. Therefore, they need to be transported from the site where they are manufactured to where they are needed in the cell or the organism. But what actually happens on a molecular level when cells transport proteins through their surrounding membranes is largely unclear.

Beyond impressive AI tools

In recent years, protein research did make tremendous strides. One notable advance is the development of AlphaFold, an AI-based tool that predicts a protein’s 3D structure from its amino acid sequence. “AlphaFold’s predictions are impressively accurate”, says Kaiser. “But it doesn’t capture the actual process, and only predicts the outcome. We still don’t really comprehend how proteins actually fold.” Therefore, what goes wrong when folding fails remains obscure.

Small errors, huge consequences

Kaiser stresses the need to delve deeper into understanding the physical principles governing protein folding, especially in the context of various diseases. Even small changes in the 3D structures of proteins can have serious health consequences. This includes diseases like several types of cancers and neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease.

Getting it right from the start

To prevent things from going awry, many proteins must start the folding process while they are ‘born’. “Protein folding is coupled to protein synthesis,” says Kaiser. “This has been known for decades. But the tools needed to study the process have become available only recently.”

The tools needed to study the process of protein folding have become available only recently.

One of these tools, developed by Kaiser’s team, allows researchers to observe single molecules. This enables direct observation of nascent protein folding on the ribosome, a cell component that synthesizes proteins.

Large proteins, which make up the majority of all human proteins, rely heavily on this mode of folding. For instance, one cause of cystic fibrosis is perturbed coupling of synthesis and folding. Kaiser’s studies promise to yield a mechanistic understanding that can then be used to rationally optimize the folding of these proteins.

Crossing the membrane

Another topic researched by Kaiser’s team is the way proteins are transported out of the cell where they originate. When a protein crosses the cell membrane, its 3D structure needs to be adjusted to align with the molecular ‘gates’ that allow protein transport. Many proteins need to be secreted through the cell membrane, to perform their duties elsewhere in the body. Examples include antibodies and collagen, the latter of which gives stability to tissues and tendons.

If we understand protein transport better, it may enable us to engineer better systems for creating therapeutic antibodies

Transport of antibodies across the cell membrane is of particular interest. “If we understand this transport process better, it may enable us to engineer better systems for creating therapeutic antibodies”, says Kaiser. Such artificial antibodies could be used to support the body’s immune system, and help combat viruses, bacteria and other pathogens.

Antibiotic resistance

Kaiser is also interested in the way bacteria transport proteins through their membranes. By secreting specific proteins into their surroundings, bacteria can develop antibiotic resistance. Kaiser: “We are in desperate need of new antibiotics. So it is very useful to study how proteins are made that mediate antibiotic resistance. Besides, many proteins that bacteria need to survive in the first place are also transported through this system. If we can find compounds that inhibit this system, we have a very effective drug against bacteria.”

If we can find compounds that inhibit this transport system, we have a very effective drug against bacteria.

Molecular chaperones

A class of helper proteins that  Kaiser particularly focusses on are so-called molecular chaperones. These are proteins that help other proteins reach and maintain their correct 3D structures, and also assist with protein transport. “We want to understand how molecular chaperones work”, says Kaiser. “We know chaperones are very important, but it’s not well understood what they actually do.”

Unraveling proteins with optical tweezers

Protein folding is very complex and quite difficult to study, says Kaiser, especially for large proteins. To understand protein folding, his team uses a technique called optical tweezers. This technique quite literally unravels single protein molecules. It uses laser beams to create mechanical forces that pull a protein on two sides, which causes unfolding.

I’m excited that my group brings this approach and the necessary skills to Utrecht University

Watching the protein unfold and fold back again, researchers can dissect the steps involved in the original folding process. It also helps to understand protein transport, since proteins have to adjust their 3D structure when they travel through the membrane. “This technique is extremely powerful”, says Kaiser. “I’m excited that my group brings this approach and the necessary skills to Utrecht University.”