Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins

Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins

Xiajun Li† and
Iva Greenwald†,‡,§,¶

^†Integrated Program in Cellular, Molecular and Biophysical Studies, ^‡Department of Biochemistry and Molecular Biophysics, and ^§Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, New York, NY 10032

Edited by Lily Yeh Jan, University of California, San Francisco, CA, and approved April 2, 1998 (received for review February 12, 1998)

Abstract

Presenilins have been implicated in the genesis of Alzheimer’s disease and in facilitating LIN-12/Notch activity during development. All presenilins have multiple hydrophobic regions that could theoretically span a membrane, and a description of the membrane topology is a crucial step toward deducing the mechanism of presenilin function. Previously, we proposed an eight-transmembrane-domain model for presenilin, based on studies of the Caenorhabditis elegans SEL-12 presenilin. Here, we describe experiments that support the view that two of the hydrophobic regions of SEL-12 function as the seventh and eighth transmembrane domains. Furthermore, we have shown that human presenilin 1 behaves like SEL-12 presenilin when analyzed by our methods. Our results provide additional experimental support for the eight-transmembrane-domain model of presenilin topology.

Footnotes

↵ ¶ To whom reprint requests should be addressed at: HHMI/Dept. of Biochemistry and Molecular Biophysics, Columbia University, 701 West 168th Street, Room 720, New York, NY 10032. e-mail: greenwald{at}cuccfa.ccc.columbia.edu.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: PS1 and PS2, presenilins 1 and 2; HR, hydrophobic region; TM, transmembrane domain.