Proteome studies of host-pathogen protein-protein interactions

We develop tailored methods for analysis of weak PPIs and PTMs at low concentrations in cells. The methods are important for understanding different diseases as infections. The research is translational and connects analytical chemistry with cell and molecular biology and medical proteomics.

Viruses infect host cells by binding to cell membrane receptors. The virus then take over the cellular machinery for replicating itself. In this process viral proteins are interacting with cellular proteins.

We work in a multidisciplinary project in systems biology funded by Swedish Foundation for Strategic Research in 2017 to elucidate the prevalence and biological roles of host-pathogen protein-protein interactions involving Short Linear Motifs (SLiMs). Pathogens mimic human SLiMs to take over the host cell machinery. They engage in interactions that are crucial for cell signaling and such interactions have crucial roles in viral infections.

SLiMs are 3-10 amino acid stretches (motifs) and in the viral proteins they serve as docking sites to human proteins (Kd ~µM, compared to the stronger affinity in domain-domain interactions of Kd nM to pM since then a longer stretch of amino acids is involved in the docking) and can be predicted by bioinformatics approaches. Mass spectrometry (MS) based proteomics analysis will be an excellent tool for identifying the interacting proteins.

A protein structure image of the amino acids that interact.
The small stretch of amino acids that interact between
the TSG101 protein and the SLiM motif PTAP peptide
in a complex gives a weak interaction. (Figure from
PDB database.) 

New enrichment/capturing methodologies for weak and transient protein-protein-interactions that we develop will allow us to investigate protein communications in a systematic way. From the analytical point of view there are no generic methods for identification of such interactions or specific methods that concludes what approach to use for different expected strengths of interactions. The main challenges to solve are how to present the motif for interacting host proteins, in as close to native conditions as possible, and how to preserve the interaction so it can be measurable. Systematic studies of such interactions are lacking today and the developments will be important to move this field forward. With the methods we develop, motifs of all possible viral proteins can be investigated. Thus, inhibitors of viral and host protein interactions are potential treatments for severe infections such as HIV, Covid-19 and Ebola. This is important for the understanding of how potent viruses hijack the cell and will provide new perceptiveness of the underlying mechanisms of infection process and novel drug targets.

Information about the project at the Swedish Foundation for Strategic Research's website (strategiska.se).

Participants in the project at the Department of Chemistry - BMC:

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