This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The human gamma-secretase plays a number of important roles in the body: it is the enzyme that becomes mutated in some familial Alzheimer's disease but its proper function is also required for the normal function of the body, such as development. This enzyme catalyzes a very unusual reaction, intramembrane proteolysis, of which we currently know very little about its mechanism. Part of the challenge is due to the fact that we do not know the structure of this enzyme and it is difficult to solve the structure of a membrane protein. To overcome this problem, we resorted to bacterial homologs of the enzyme and now we have obtained diffracting crystals of the bacterial protein. We plan to collect x-ray diffraction data from these crystals and solve the structure of this membrane protein. This work is likely to shed light on the mechanism of intramembrane proteolysis and allow us to understand how changes affecting this memchanism can cause Alzheimer's disease.
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