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Exploring Transport Cycle Conformational Changes

ATP Binding Cassette (ABC) transporters constitute one of the largest families of membrane proteins, and translocate across membranes a wide variety of substrates, from ions to metabolites, sugars, drugs, lipids, sterols or peptides. ABC transporters are involved in many physiological processes in the human cells, and mutations in the genes encoding many of these transporters are associated with several diseases, such as cystic fibrosis, Tangier disease, and diabetes. An over-expression of certain ABC transporters contributes to cancer drug resistance as well as resistance to other cytotoxic agents.

Due to the medical relevance of these transporters, a detailed knowledge of the molecular basis of their mechanism of action is essential. Valentina Corradi is using computer simulations and detail-rich modeling tools to gain deeper insight into the conformational changes of transmembrane and cytosolic domains during their transport cycle.

ATP binding and hydrolysis occur on the cytosolic domains, and are coupled with the conformational changes of the transmembrane domains to allow substrate translocation. Corradi’s models are used to study the dynamics of the conformational changes, and to identify transitions between different crystallographic states. Her findings will help researchers better understand the structure-function relationships of the ABC transporters as well as specific features of individual transporters, such as the human ABC transporter associated with antigen processing (TAP). TAP plays an essential role in the antigen presentation mechanism by translocating antigenic peptides from the cytosol into the endoplasmic reticulum lumen.