RAS is a protein that is integral to the mitogen activating pathway (MAP) that controls cell growth and division. Mutations in RAS deregulate the pathway, which can result in cancer. When bound to the substrate GTP, RAS is activated; when bound to the substrate GDP, RAS is deactivated. The substrate bound to RAS catalyzes conformation changes in two switch regions, which coordinate the interaction RAS has with its substrate. To switch between GTP and GDP, RAS requires assistance from other proteins. GEFs activate RAS by exchanging GDP for GTP; GAPs deactivate RAS by assisting in GTP hydrolysis. The Moeller SMART Team in conjunction with MSOE Center for Biomolecular Modeling used 3‐D modeling and printing technology to pinpoint amino acids that play a crucial role in RAS GTP to GDP exchange. Our mentor, Dr. Nicolas Nassar, created RAS mutations and observed the effect they had on RAS. In these mutations, the two switch regions are restructured, which affects the MAP activity. This alters Mg2+ ion coordination and guanine nucleotide stabilization. These mutations also prevent the coordination of the catalytic water molecule responsible for the hydrolysis of GTP. In mutated RAS, GEFs are not able to exchange GDP for GTP. These mutants transform RAS to stay active longer compared to wt‐RAS. By learning about RAS GTP and GDP exchange, Dr. Nassar hopes to dock a small molecule into the binding site of cancerous RAS thus inhibiting the mitogen activating pathway.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Moeller SMART Team in conjunction with Dr. JiaJie Diao at the University of Cincinnati Medical College and MSOE Center for Biomolecular Modeling used 3‐D modeling and printing technology to study the role of misfolded alpha‐synuclein proteins in Parkinson’s Disease (PD). Neurodegenerative diseases are all characterized by the aggregation of misfolded proteins that form an insoluble substrate. Misfolded alpha‐synuclein is thought to be the protein involved in PD. This protein is natively found as an unfolded monomer that can take on many different conformations. It consists of 140 amino acids and is divided into three regions: the N‐terminal region (residues 1–60), non‐amyloid beta component (NAC) (residues 61–95), and the C‐terminus (residues 96–140). Alpha‐synuclein shows the ability to form amyloid fibrils which are associated with toxicity. Subunits within the fibrils adopt a beta‐strand conformation with hydrogen bonding between adjacent beta strands to form long linear polymers. The N‐terminal and C‐terminal residues display a random coil arrangement that are not involved in hydrogen bonding. The central beta sheet core is comprised of an inner hydrophobic region that interlocks into compact right‐angled spirals. Each fibril can form a dimer with rotational symmetry about the bonding interface. Within the beta sheet region, the NAC and pre‐NAC regions are responsible for fibril formation. The NAC region is the central hydrophobic region that when removed from alpha‐synuclein leads to the inability of aggregation.
The Moeller SMART Team in conjunction with Dr. JiaJie Diao at the University of Cincinnati Medical College and MSOE Center for Biomolecular Modeling used 3‐D modeling and printing technology to study the role of Soluble NSF Attachment Protein Receptor (SNARE) proteins in macroautophagy, a process that recycles damaged organelles, proteins, and microbes in the cell. It begins with the formation and maturation of an autophagosome. The process ends with the fusion of a fully matured autophagosome to a lysosome membrane, which is mediated by SNARE proteins. Vesicular fusion is initiated by the formation of a tetrameric alpha‐helix complex that is formed through the binding of three helical SNARE proteins. One of these SNARE proteins, VAMP8, is located on lysosomes and the other two, syntaxin17 and SNAP‐29, are located on the membrane of autophagosomes. The helices of these proteins coil tightly in the alpha‐helix complex which provides the energy for fusion. To reset the conformation of SNARE proteins, N‐Ethylmaleimide‐Sensitive Factor (NSF) proteins use ATP and water to recycle SNAREs. Alpha‐SNAP, an ATPase, which helps to facilitate this process, returns SNARE to its original high energy state. If fusion is unable to occur in autophagy, the cell accumulates autophagosomes, causing lysosome storage diseases such as Parkinson's and Alzheimer's disease. By 3‐D printing the coiled alpha‐helix complex, our SMART team intends to describe this crucial element of membrane fusion and the disorders associated with macroautophagy. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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