A novel transmembrane topology of presenilin based on reconciling experimental and computational evidence

The transmembrane topology of presenilins is still the subject of debate despite many experimental topology studies using antibodies or gene fusions. The results from these studies are partly contradictory and consequently several topology models have been proposed. Studies of presenilin‐interacting proteins have produced further contradiction, primarily regarding the location of the C‐terminus. It is thus impossible to produce a topology model that agrees with all published data on presenilin. We have analyzed the presenilin topology through computational sequence analysis of the presenilin family and the homologous presenilin‐like protein family. Members of these families are intramembrane‐cleaving aspartyl proteases. Although the overall sequence homology between the two families is low, they share the conserved putative active site residues and the conserved ‘PAL’ motif. Therefore, the topology model for the presenilin‐like proteins can give some clues about the presenilin topology. Here we propose a novel nine‐transmembrane topology with the C‐terminus in the extracytosolic space. This model has strong support from published data on γ‐secretase function and presenilin topology. Contrary to most presenilin topology models, we show that hydrophobic region X is probably a transmembrane segment. Consequently, the C‐terminus would be located in the extracytosolic space. However, the last C‐terminal amino acids are relatively hydrophobic and in conjunction with existing experimental data we cannot exclude the possibility that the extreme C‐terminus could be buried within the γ‐secretase complex. This might explain the difficulties in obtaining consistent experimental evidence regarding the location of the C‐terminal region of presenilin.