Protein structure shapes biological function. When a protein changes conformation, the effects can spread from a single molecule to cells, tissues, and organs.
Konstantinos Thalassinos, Professor of Mass Spectrometry and Academic Lead at the Institute of Structural and Molecular Biology at University College London, compares proteins to instruments in an orchestra. The way an instrument is built determines the sound it produces. A small defect can alter that sound and disrupt the wider performance.
Protein misfolding follows a similar pattern. A protein adopts the wrong conformation, begins to associate with other misfolded proteins, and forms larger aggregates. These aggregates can disrupt cellular processes, contribute to cell death, and drive disease.
A Shared Mechanism Across Major Diseases
Protein misfolding and aggregation contribute to several serious conditions, including Alzheimer’s disease, Huntington’s disease, type 2 diabetes, and alpha-1 antitrypsin deficiency.
Although these diseases involve different proteins and affect different organs, they share a common process. A normally functioning protein changes conformation, begins to aggregate, and triggers biological damage.
These structural changes remain difficult to study. Misfolded proteins can occupy several conformations and move between them within short timeframes. Traditional structural biology methods often struggle to capture these transient intermediates.
Computational tools can predict stable protein structures from amino acid sequences. However, researchers still need experimental measurements to identify fast-changing or coexisting conformational states.
Capturing Early Misfolding Events
Thalassinos and his colleagues have spent more than a decade studying alpha-1 antitrypsin, a protein produced mainly in the liver and transported to the lungs, where it helps protect tissue from enzyme damage.
In alpha-1 antitrypsin deficiency, the protein misfolds and becomes trapped in the liver. This process can contribute to liver disease while reducing the amount of functional protein available to protect the lungs.
The team began studying the protein using an earlier-generation Synapt ion mobility mass spectrometry platform. Later improvements in instrument sensitivity allowed the researchers to examine early misfolding intermediates that had not been characterized before.
The researchers also investigated the structure of the protein dimer, which forms when two protein molecules associate. This stage represents one of the earliest steps in the polymerization pathway that leads to larger aggregates.
Ion mobility mass spectrometry separates protein species based on factors such as size, shape, and charge. This capability allows researchers to distinguish structural forms that may appear similar through mass measurement alone.
Moving Closer to Disease Biology
The group aims to connect analytical measurements with real biological questions. Its work has moved beyond purified model proteins toward clinically relevant material.
This includes alpha-1 antitrypsin isolated from liver tissue associated with transplantation. These samples allow researchers to compare laboratory findings with the molecular forms present in disease.
Progress depends on collaboration across several fields. Instrument manufacturers must continue improving sensitivity, resolution, and dynamic range. Analytical researchers must develop methods that translate these capabilities into biological insight. Clinicians provide disease expertise and access to relevant samples. Therapeutic researchers can then use these findings to explore potential interventions.
Examining the Wider Cellular Response
The research also extends beyond the first stages of protein misfolding. Thalassinos and his team want to understand how the rest of the cell responds once abnormal protein conformations begin to appear.
Using the orchestra analogy, the goal involves identifying both the first wrong notes and the effect they have on the wider performance.
The group continues to study alpha-1 antitrypsin and applies similar methods to amylin, a peptide associated with type 2 diabetes. It also runs a major research program focused on Huntington’s disease and the proteins involved in expanded nucleotide repeats and toxic huntingtin formation.
These projects show how ion mobility mass spectrometry can help structural biologists study transient protein states, investigate disease mechanisms, and connect molecular changes with wider cellular effects.
By capturing conformations that other methods may miss, researchers can build a clearer picture of how protein misfolding begins, how it progresses, and where future therapies may intervene.
