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Three-dimensional dynamic views of proteomes as a novel readout for physiological and pathological alterations

Periodic Reporting for period 2 - Proteomes-in-3D (Three-dimensional dynamic views of proteomes as a novel readout for physiological and pathological alterations)

Okres sprawozdawczy: 2021-09-01 do 2023-02-28

Systems biology of proteins classically uses a technique called proteomics, which measures thousands of proteins in a biological system at once. This is very powerful, but it does not look at the structures (i.e. shapes) of these proteins, but only at their amounts. However, protein structures are critically important to understand how proteins function in health or mis-function in disease. The Picotti lab is solving this problem by developing an approach to study the structure and function of thousands of proteins at the same time, within their native biological context. The lab applies these methods to study protein aggregation (a type of protein structural change), in particular in diseases that are linked to aggregation such as the neurodegenerative Parkinson’s disease (PD). The overall goal of the project is to probe the role of protein aggregates or assemblies in healthy physiology and in disease, and also to extend the functional and mechanistic knowledge obtainable from systems biology. It will advance our basic knowledge of biological mechanisms, teach us about the new and exciting area of functional protein aggregates, and shed light on the prevalent and growing class of aggregation-based diseases.
In this phase of the project we have shown that global protein structural information (ie structures of thousands of proteins) detects multiple functional molecular events in the cell, for example enzyme catalysis and protein-protein interaction (among others). So for the first time, with a single analysis, we can monitor multiple different molecular processes going on in the cell and watch what happens when the cell changes. We have also shown that our global structural readout can be used to help identify drug targets and off-targets in mammalian cells, which is of interest in biopharma. Finally, we have shown that a global structural analysis of proteins in human cerebrospinal fluid better distinguishes between Parkinson’s patients and healthy individuals than a standard analysis of protein amounts; this finding could form the basis of a new type of disease biomarker to diagnose the disease early and to select appropriate treatments. Finally, we have also studied the biological effects of various normal and disease-related protein aggregates in yeast cells.
Our work demonstrates the new concept that global protein structural analysis is more powerful than classical abundance-based proteomics for learning functional information, at the molecular level, both when studying organisms like yeast cells in the laboratory and in diagnosis and study of human disease. In ongoing work, in addition to making many further technical developments, we are building a new atlas of protein structural dynamics, which will enrich the state of the art protein atlases by bringing in the element of structural change. We are also using our global analysis to study protein aggregation during mammalian aging, a process that is well known to occur but where the relevance for the organism is not well understood. Finally we are using the detailed molecular information that we can gain with our approach to model biological processes. We expect by the end of the project to have both a better understanding of the role of protein aggregation in health and disease and to improve substantially our ability to marry molecular and global understanding of biological systems.