Biomolecular networks in health and disease
The Gavin group integrates proteomics, metabolomics, and biochemical and microfluidics-based methods to achieve a systems-level understanding of how cellular proteomes are organised.Edit
Biological function arises from the concerted actions of interacting proteins (and other biomolecules) that assemble into protein complexes and larger networks. In model organisms and human pathogens, our past breakthroughs have demonstrated that protein complexes represent the smallest, conserved units of proteome organization that participate in all major cellular processes (Gavin et al., Nature 2002; Gavin et al., Nature 2006; Kuhner et al., Science 2009).
Our current interest concerns metabolism and its spatio-temporal organization. The central role of metabolism has led to intense efforts dedicated to characterizing the sequence of chemical reactions, and cataloguing the metabolome. However, the spatial organization of these metabolic pathways within cells and the transport of metabolites, which can be highly labile or even toxic, remain largely understudied. Lipids represent a particularly interesting case. All aspects of lipid function rely on their heterogeneous distribution within biological systems, where their local accumulation defines specific organelle membranes or organise signalling pathways. Because of their hydrophobic nature, lipids cannot freely diffuse in aqueous phases and the pathways in which they are involved – scattered over distinct organelles – require still elusive transport mechanisms. An emerging player in these processes is a group of >100 disease-associated proteins known as lipid-transfer proteins (LTPs). They spatially organise lipids and connect lipid metabolic pathways (distributed across distinct organelles), but our knowledge of these mechanisms remains fragmented. We have developed new technologies to produce systematic datasets measuring protein-lipid interactions in a systematic manner (Maeda et al., Nat Protoc 2014; Saliba et al., Nat Methods 2014; Saliba et al., Nat Protoc 2016) and recently published proof-of-principle studies (Vonkova et al., Cell Rep 2017). They led to the discovery of new routes of phosphatidylserine transport (Maeda et al., Nature 2013) and – with the group of Martin Beck – of a metabolon implying a mechanism of direct substrate channelling from a carboxylase to the fatty acid synthase (Kastritis et al., Mol Syst Biol. 2017).
Our unpublished data, supports the existence of many new pathways of LTP-mediated lipid movements in human cells, which need to be explored and placed into their (sub)cellular and metabolic, signalling contexts and this represents our immediate goal. The mechanistic and structural insights into the processes of specific membrane recognition and lipid transfer will inform on the impact of disease mutations and will be used to engineer chemical probes. The group is also partially associated with the Molecular Medicine Partnership Unit (University Heidelberg) to study the molecular mechanisms affected by ageing.