FASEB - Protein Folding in the Cell

The Federation of American Societies for Experimental Biology is celebrating its 100th year and recently organised a conference to discuss one of the most fundamental puzzles of cell biology; how do proteins fold and become functional in such a crowded environment?

Name: Priyanka Narayan

Date: 29th July to 3rd August 2012

Location: Saxton's River, Vermont, US

Website: http://www.faseb.org/Home.aspx

The field of protein folding has flourished since Christian Anfinsen first suggested that a long chain of chemically distinct amino acids could "encode" the fold of a structured functional protein. Many have explored the diversity of shapes and folding mechanisms of proteins in the test tube. These studies have led to a wealth of data and knowledge on how an unfolded string of amino acids achieves a functional folded state.

However, what has yet to be adequately addressed is that the process of protein folding most often occurs within a cell, an environment far more crowded and chaotic than anything found in a test tube. This FASEB SRC conference sought to address this emerging topic: "How does a protein fold in a cellular environment," and the associated medical question, "what happens when this process does not proceed correctly and how does the cell handle this?"

The talks and posters in the conference covered topics from the birth of a protein (looking at folding on the ribosome) to the degradation of both folded and misfolded proteins. Many examined the role of stress in dictating which pathways were used in protein quality control and hoped to relate those effects to changes with age and disease.

As my work has primarily focused on in vitro studies of protein misfolding and aggregation, I was truly amazed, as I walked through the posters and listened to talks, at the sheer wealth of quality control mechanisms at play in a single cell. All of these systems, many of which are new and poorly understood, work to ensure that a protein does not undergo detrimental misfolding process or persist in a potentially toxic misfolded or aggregated state. The advent of new biophysical technologies such as advanced coarse-grained simulations, single-molecule techniques, and in-cell NMR have equipped researchers to glean a quantitative perspective on protein folding and quality control within the cell.

A key theme of the conference was that there needs to be an integration of in vitro and in vivo data in order for us to be able to really understand protein folding in cells. Molecular mechanism and intermolecular interactions have most commonly been elucidated using a "bottom-up" approach, by looking at roles of individual proteins and slowly adding in partners to deduce the function of protein complexes. However, the need to examine entire cellular systems simultaneously has become evident, necessitating a "top-down" approach using broad-based techniques such as proteomic profiling of whole organisms allowing the deduction of interaction networks within cells. This would also allow more accurate modelling of the effects of changing the state of one network member on the rest of the cellular components. The concurrent use of both approaches (bottom-up and top-down) can help to derive a mechanistic understanding of how simple changes result in complex, disease-related phenotypes.

This integration of approaches is only possible with cooperation between scientists and labs with varied expertise. One especially remarkable aspect of this meeting was in the diversity of approaches presented. From both posters and talks, we heard about a number of techniques from computational modelling to organismal proteomics to in-cell NMR and electron microscopy, all used to understand various aspects of protein quality control. This aspect of the conference not only gave me an exposure to what is possible using these techniques but also showed me the power of collaboratively using different approaches and expertise together to understand complex cellular systems.

Overall, the FASEB SRC was a fantastic meeting bringing together those interested in protein folding and quality control from basic scientific and clinical disease-oriented perspectives. The meeting reviewed and highlighted the diversity of innovative new techniques available to cellular biologists and biophysicists today. It also helped outline the primary challenges in understanding how proteins are managed in a cellular environment and the importance of integrating a systemic perspective on the problem. The SRC environment encouraged dialogue and collaboration between those with different perspectives and provided a launching pad for future research into the complexity of protein folding and regulation in the cell.

(Images from conference website and DrKjaergaard via Wikimedia Commons)