A single conserved proline residue determines the membrane topology of stomatin.

Stomatin is an integral membrane protein which is widely expressed in many cell types. It is accepted that stomatin has a unique hairpin-loop topology: it is anchored to the membrane with an N-terminal hydrophobic domain and the N- and C-termini are cytoplasmically localized. Stomatin is a prototype for a family of related proteins, containing among others MEC-2 (mechanosensory protein 2) from Caenorhabditis elegans, SLP (stomatin-like protein)-3 and podocin, all of which interact with ion channels to regulate their activity. Members of the stomatin family partly localize in DRMs (detergent-resistant membrane domains) enriched in cholesterol and sphingolipids. It has been proposed that a highly conserved proline residue in the middle of the hydrophobic domain directly binds cholesterol and that cholesterol binding is necessary for the regulation of ion channels. In the present study we show that a small part of the stomatin pool exists as a single-pass transmembrane protein rather than a hairpin-loop protein. The highly conserved proline residue is crucial for adopting the hairpin-loop topology: substitution of this proline residue by serine transfers the whole stomatin pool to the single-pass transmembrane form, which no longer localizes to DRMs. These results suggest that formation of the hairpin loop is inefficient and that the conserved proline residue is indispensable for formation of the hairpin loop. The single-pass transmembrane form exists also for SLP-3 and it should be considered that it mediates part of the physiological functions of stomatin and related proteins.

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