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Flippin’ Lipids John DeVroy, Kevin Patel, Ronak Patel, Fred Seewald, Beth Stebbins, April Szfranski, Jazzmyne Washington, Mike Weber Mentor: Candice Klug, Ph. D., Medical College of Wisconsin Teacher: Mrs. Jean Lee 1 ABSTRACT MsbA is a member of the ABC transporter class of proteins‐one of the largest found in nature. ABC transporters move solutes across the cell membrane. MsbA consists of two transmembrane domains and two nucleotide binding domains. The transmembrane domains consist of 6 α‐helices embedded in the phospholipid bilayer. The nucleotide binding domains are found in the cytosol and are the site of ATP hydrolysis, which provides the energy for the protein to function. MsbA is a lipid flippase, which means it transports lipid A produced in the cytosol to the outer leaflet of the inner cell membrane, flipping it so the hydrophilic end faces out. Lipid A is essential to the outer cell membrane of Gram‐negative bacteria, but if MsbA does not function properly, lipid A can kill the bacteria by accumulating in the intracellular layer of phospholipids. This is important to researchers as MsbA has homology to human multidrug resistance proteins. Finding a way to render MsbA inactive could lead to not only antibiotics for Gram‐negative bacteria such as Salmonella, but also as a solution to chemotherapy drug resistance. Before After Periplasm ¾Lipid A is an essential component of the outer surface of the bacterial cells, within their inner membranes. ¾Lipid A is synthesized in the cytoplasm of the cell and inserted into the inner cell membrane. ¾Here (at the inner membrane), when lipid A binds to MsbA, the lipid is ‘flipped’ from facing the cytosol to the periplasm. Intracellular ¾Although MsbA does not flip itself, it works as a pair of scissors to transport lipid A. 2 ATP = Lipid A 3 ¾This energy (from ATP) induces the conformational change, forcing MsbA’s two dimers to come close together on the inner side and open in the periplasm. ¾When Lipid A is bound to MsbA during ATP binding or hydrolysis, it is ‘flipped’ to the periplasmic side of the membrane ¾Adenosine triphosphate (ATP) binds to the Nucleotide Binding Domain NBD. ¾This binding causes ATP to undergo hydrolysis where ATP breaks down to adenosine diphosphate (ADP) and a phosphate. ¾This process releases energy to MsbA. 4 5 PDB ID 3B5Z.pdb http://elementy.ru/news/430238 http://www.zimbio.com/Salmonella+in+Peanut+Butter/articles/48/Sa lmonella+Peanut+Butter+Recall+2009 http://faculty.uca.edu/~benw/biol1400/notes32.htm http://www.stpaulsmtl.wa.edu.au/teachers/energy/energizer_bunn y.jpg http://www.hotrodlane.cc/61HEMI?C=S;O=D Ward, A., Reyes, C. L., Yu, J., Roth, C. B., and Chang, G. (2007) Flexibility in the ABC transporter MsbA: Alternating access with a twist. PNAS 104, 19005‐19010. = Lipid A MsbA is an ABC transporter that transfers lipid A, found in the inner membranes of Gram‐negative bacteria from the cytosol to the periplasm. So, if this process of transporting lipid A does not occur then a toxic amount of lipid A can accumulate in the intracellular layer of phospholipids and cause the bacterial cell to die. This is important to researchers because finding a way to render MsbA inactive could lead to not only antibiotics for Gram‐negative bacteria such as Salmonella, but also as a solution to chemotherapy drug resistance. A SMART Team project supported by the National Institutes of Health (NIH) –National Center for Research Resources Science Education Partnership Award (NCRR‐SEPA)
