This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The function of diphtheria toxin T-domain (DTT) is to translocate the catalytic domain of the toxin across the lipid bilayer in response to acidification of the endosome, a mode of entry shared by a number of bacterial toxins, including the potential bioweapon botulinum. Despite the progress in characterization of membrane interactions of DTT, the molecular mechanism of its action and the structure of DTT in its functional membrane-inserted form remain unknown. Hemifluorinated compounds, such as HF-TAC, are a novel class of non-detergent surfactants designed to amend solubilization of membrane proteins for functional and structural studies. Because DTT, depending on pH, can be found in both an insertion-competent and water-soluble form, it presents a convenient model for studying the general effects of these surfactants on the membrane protein insertion/folding pathway. The objective of this grant is to determine the mode of interaction of surfactants with DTT using site-directed fluorescence labeling and other spectroscopic approaches.
The specific aims are: (1) determine the effect of HF-TAC on the aggregation state of DTT; (2) determine the effect of HF-TAC on the free energy of membrane association of DTT; (3) determine the effect of HF-TAC on DTT-induced membrane disruption; (4) determine the direct effect of HF-TAC on the integrity of the lipid vesicles. This study will lay the groundwork for subsequent high resolution structural studies of DTT in membrane environment.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-8 (01))
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University of Kansas
Schools of Medicine
Kansas City
United States
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