What is α-synuclein when it’s not aggregated?

In a recent paper in PNAS, co-lead authors Wei Wang (Indiana U. School of Medicine) and Iva Perovic (Chemistry Ph. D. program, Brandeis), together with researchers from Brandeis, Indiana, Scripps, NIH, Washington State, and Harvard, investigated the structure of the abundant small neuronal protein α-synuclein. α-Synuclein has been strongly associated with the disease process in Parkinson disease, both from histology (found in aggregates in Lewy bodies associated with disease) and from genetics (mutations in the gene associated with a rare familial form of Parkinson disease). The structure and function of α-synuclein is not well understood. It is an abundant neuronal protein, and appears to bind to lipids, vesicles, and plasma membrane. Heterologously expressed α-synuclein is often observed to be unfolded, and the biochemical role of the protein is still unidentified.

In this new study, α-synuclein was expressed as a GST fusion protein in E. coli and proteolytically cleaved to form α-synuclein with a 10 amino acid N-terminal extension. This protein was shown to form a stable tetrameter with alpha-helical content in the absence of lipids, using a combination of many techniques, including NMR spectroscopy, electron microscopy, circular dichroism and mass spectroscopy of cross-linked products. The authors combined this information to propose a model for the structure of native α-synuclein when it is not aggregated that is a tetramer based on amphipathic central helices.

Researchers in the Pochapsky, Petsko-Ringe and Agar labs at Brandeis participated in the study. Future work is aimed at understanding the function of this tetrameric form of the protein, with the hope of developing techniques to stabilize it and determine its function. For more information and interview with the authors, see the story at BrandeisNOW.


Spring-loading the active site of cytochrome P450

Enzymes differ from other catalysts in the exceptional substrate selectivity they exhibit.  However, the active sites of related enzymes are often very similar, even though different substrates are acted upon (for example in the superfamily of cytochrome P450s).  How does a given enzyme preferentially bind a particular substrate?  In a new paper appearing in the jounal Metallomics, Chemistry grad student Marina Dang and Profs. Susan Sondej Pochapsky and Thomas Pochapsky use nuclear magnetic resonance (NMR) to identify a helical structure remote from the active site of the enzyme cytochrome P450cam that is responsive to changes in substrate.  They propose that this helix can adjust the position of residues that contact substrate in the enzyme active site, much like the spring that holds batteries in place against electrical contacts in a flashlight.

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