Landreh lab

Popular science presentation

Research in my lab focuses on understanding how proteins interact and function within the cell—a key to decoding life’s molecular mechanisms. Using so-called native mass spectrometry (MS), we can study entire protein complexes. By gently transferring them into the gas phase with electrospray ionization, we can directly observe how proteins bind to each other, change shape, and form stable or transient structures.

My lab develops new methods to improve our ability to analyze complex biological systems. This includes studies of how proteins become ionized, how their structure is preserved in the gas phase, and how computational models can be used to interpret results to reveal details about binding and dynamics.

We also integrate mass spectrometry with AI-based structural biology and techniques such as cryo-electron microscopy and X-ray crystallography. This combination makes it possible to build structural and functional models of proteins with near-atomic precision, and to use MS to verify computational predictions.

Finally, the technology is used to study disease-related protein complexes, such as those associated with cancer and neurodegeneration, as well as the phenomenon of liquid–liquid phase separation (LLPS)—the process behind the formation of the cell’s membraneless organelles. Together, these studies provide a deeper understanding of how proteins organize themselves, cooperate, and sometimes malfunction—knowledge that can ultimately pave the way for new medical treatments.

Research projects

Mass Spectrometric Method Development

A central focus of the lab is to explore and expand the capabilities of ESI and mass spectrometry to analyze complex biological systems. This includes studying the principles that govern ionization, evaluating their impact on dynamic and labile protein interactions, and developing strategies to preserve and modulate protein structures in the gas phase. We routinely employ computational tools to aid the interpretation of MS data, allowing precise characterization of protein stoichiometry, ligand binding, and dynamic conformational changes.

https://pubmed.ncbi.nlm.nih.gov/40369858/

https://pubmed.ncbi.nlm.nih.gov/34977906/

https://pubmed.ncbi.nlm.nih.gov/33439171/

https://pubmed.ncbi.nlm.nih.gov/30927297/

Mass Spectrometry of Membrane Proteins

Membrane proteins are essential for cellular communication, transport, and signaling, yet their hydrophobic nature makes them challenging to study using traditional structural methods. We have a long-standing interest in mass spectrometric techniques that enable the analysis of how lipids, cofactors, and small molecules modulate membrane protein structure and stability. Work in this area includes the use of protein design tools to uncover first principles of membrane protein stability and how it is governed by specific lipid interactions.

https://pubmed.ncbi.nlm.nih.gov/35424940/

https://pubmed.ncbi.nlm.nih.gov/32371966/

https://pubmed.ncbi.nlm.nih.gov/31886601/

https://pubmed.ncbi.nlm.nih.gov/40304703/

Integrating Mass Spectrometry with AI-guided Structural Biology

To understand the structure-function relationship of complex protein systems, we combine native MS with complementary techniques such as cryo-electron microscopy (cryo-EM), X-ray crystallography and NMR spectroscopy. We routinely use machine learning to build comprehensive models of protein structure and dynamics. By correlating mass spectrometry data with high-resolution models from AlphaFold and related tools, we can achieve a near-atomic understanding of protein complexes, making use of the unique suitability of MS to verify AI predictions.

https://pubmed.ncbi.nlm.nih.gov/36115577/

https://pubmed.ncbi.nlm.nih.gov/35634779/

https://pubmed.ncbi.nlm.nih.gov/39299235/

https://pubmed.ncbi.nlm.nih.gov/40570050/

Mass Spectrometry of Biological Assemblies in Cancer and Neurodegeneration

One of the core strengths of native MS is its ability to capture dynamic and large biological assemblies such as chaperone systems and transcription factor complexes which play outsized roles in neurodegeneration and cancer. We therefore use MS to explore how these proteins form functional architectures, how subunits interact and exchange, and how these assemblies respond to environmental changes. Understanding the assembly and regulation of these complexes provides key insights into cellular processes and the molecular basis of diseases driven by protein misfolding or aggregation. We are particularly interested in the MYC proto-oncoprotein, the p53 tumor suppressor, and the BRICHOS and Nucleophosmin chaperones, where we use MS to explore strategies to modulate their stability and function for therapy.

https://pubmed.ncbi.nlm.nih.gov/38424045/

https://pubmed.ncbi.nlm.nih.gov/40406608/

https://pubmed.ncbi.nlm.nih.gov/35290795/

https://pubmed.ncbi.nlm.nih.gov/36743470/

Liquid-liquid phase separation through the lens of native MS

A growing area of interest in the lab is the study of liquid–liquid phase separation (LLPS)—a fundamental mechanism that drives the formation of membraneless organelles such as stress granules and nucleoli. We recently established a native MS and microscopy-based strategy to examine how proteins interact to form condensates, and how ligands or mutations influence their assembly and dissolution. By capturing the molecular composition and dynamic exchange of components within phase-separated systems, native MS offers an unparalleled view of the early molecular events that lead to condensation. We are now using our approach to study LLPS in a wide range of systems from spider silk to designed drug delivery condensates.

https://pubmed.ncbi.nlm.nih.gov/37084706/

https://pubmed.ncbi.nlm.nih.gov/37145883/

https://pubmed.ncbi.nlm.nih.gov/37907762/

https://pubmed.ncbi.nlm.nih.gov/37439740/

https://pubmed.ncbi.nlm.nih.gov/39533043/