Membrane Topology of the C. elegans SEL-12 Presenilin

Abstract

Mutant presenilins cause Alzheimer's disease. Presenilins have multiple hydrophobic regions that could theoretically span a membrane, and a knowledge of the membrane topology is crucial for deducing the mechanism of presenilin function. By analyzing the activity of beta-galactosidase hybrid proteins expressed in C. elegans, we show that the C. elegans SEL-12 presenilin has eight transmembrane domains and that there is a cleavage site after the sixth transmembrane domain. We examine the presenilin sequence in view of the predicted topology and discuss possible mechanisms for presenilin function.

HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling

“…Our results suggest that the amino terminus, loop, and carboxyl terminus of HOP-1 are all cytosolic (Fig. 3), as they are in other presenilins (8,9).…”

“…The amino and carboxyl termini of SEL-12 and PS1 are cytosolic, as is a large intracellular loop located between the sixth and seventh transmembrane domains (8,9). We have determined that HOP-1 has these essential features of presenilin topology by using the LacZ hybrid protein approach that we used to deduce the topology of SEL-12 presenilin (9).…”

“…Glp-1, phenotypes associated with the reduction of glp-1 activity: defective germ line proliferation and premature entry of germ cells into meiosis, or missing anterior pharynx (25,26). Lag, phenotypes associated with the concomitant reduction of lin-12 and glp-1 activity: missing rectum and͞or excretory cell (27 (9). Most of the sequence divergence is found in two cytosolic regions, one at the amino terminus and the other in the loop between the sixth and seventh transmembrane domains.…”

“…Most of the sequence divergence is found in two cytosolic regions, one at the amino terminus and the other in the loop between the sixth and seventh transmembrane domains. This region of the loop has features reminiscent of a PEST [region rich in proline (P), glutamate (E), serine (S), and threonine (T)] protein destabilization sequence (9). HOP-1 is similar to the other presenilins in terms of the overall length and spacing of the transmembrane domains, the presence of a PEST sequence between the sixth and seventh hydrophobic domains, and the presence of a hydrophobic region following the eighth transmembrane domain.…”

“…SEL-12 appears to be a bona fide presenilin, because human PS1 and PS2 can rescue the Egl phenotype of a sel-12 mutant (7). Furthermore, the membrane topology of SEL-12 and PS1 appears to be similar (8)(9)(10). In addition to the functional and structural similarities, expression studies indicate that SEL-12 and human presenilins are expressed throughout development in many different cell types (3,4,7).…”