tailieunhanh - Báo cáo khoa học: 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 conse-quently several topology models have been proposed. Studies of preseni-lin-interacting proteins have produced further contradiction, primarily regarding the location of the C-terminus. | ềFEBS Journal A novel transmembrane topology of presenilin based on reconciling experimental and computational evidence Anna Henricson Lukas Kall and Erik L. L. Sonnhammer Center for Genomics and Bioinformatics Karolinska Institutet Stockholm Sweden Keywords presenilin c-secretase presenilin-like protein topology prediction transmembrane topology Correspondence E. Sonnhammer Center for Genomics and Bioinformatics Karolinska Institutet S-171 77 Stockholm Sweden Fax 46 8337983 Tel 46 852486395 E-mail Received 25 January 2005 revised 22 March 2005 accepted 31 March 2005 doi 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 preseni-lin-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 preseni-lin-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 c-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

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