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J. Biol. Chem., Vol. 278, Issue 9, 6803-6808, February 28, 2003

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The Transmembrane Domain of the Amyloid Precursor Protein in Microsomal Membranes Is on Both Sides Shorter than Predicted^*

Beate Grziwa^§, Marcus O. W. Grimm, Colin L. Masters^¶, Konrad Beyreuther, Tobias Hartmann, and Stefan F. Lichtenthaler^**

From the  Center for Molecular Biology Heidelberg, University of Heidelberg, INF 282, D-69120 Heidelberg, Germany, the ^¶ Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia, and the ^** Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114

The amyloid precursor protein is cleaved within its ectodomain by -amyloid-converting enzyme (BACE) yielding C99, which is further cleaved by -secretase within its putative transmembrane domain (TMD). Because it is difficult to envisage how a protease may cleave within the membrane, alternative mechanisms have been proposed for -cleavage in which the TMD is shorter than predicted or positioned such that the -cleavage site is accessible to cytosolic proteases. Here, we have biochemically determined the length of the TMD of C99 in microsomal membranes. Using a single cysteine mutagenesis scan of C99 combined with cysteine modification with a membrane-impermeable labeling reagent, we identified which residues are accessible to modification and thus located outside of the membrane. We find that in endoplasmic reticulum-derived microsomes the TMD of C99 consists of 12 residues that span from residues 37 to 48, which is N- and C-terminally shorter than predicted. Thus, the -cleavage sites are positioned around the middle of the lipid bilayer and are unlikely to be accessible to cytosolic proteases. Moreover, the center of the TMD is positioned at the -cleavage site at residue 42. Our data are consistent with a model in which -secretase is a membrane protein that cleaves at the center of the membrane.

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