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1 GTTB/NIDCR, National Institutes of Health, Bethesda, MD, USA
* To whom correspondence should be addressed. E-mail: yoh{at}mail.nih.gov.
The polytopic membrane protein presenilin 1 (PS1) is a component of the 
-secretase complex that is responsible for the intramembranous cleavage of a number of type I transmembrane proteins including the 
-amyloid precursor protein (APP). Mutations of PS1, apparently leading to aberrant processing of APP, have been genetically linked to early-onset familial Alzheimer's disease. PS1 contains ten hydrophobic regions (HRs) sufficiently long to be 
-helical membrane spanning segments. Most topology models for PS1 place its C-terminal ~40 amino acids, which include the 10th HR, in the cytosolic space. However, several recent observations suggest that HR 10 may be integrated into the membrane and involved in the interaction between PS1 and APP. We have applied three independent methodologies to investigate the location of HR 10 and the extreme C-terminus of PS1. The results from these methods indicate that HR 10 spans the membrane and that the C-terminal amino acids of PS1 lie in the extra-cytoplasmic space.
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