. Membrane topology of gamma-secretase component PEN-2. J Biol Chem. 2003 May 30;278(22):20117-23. PubMed.


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  1. Pen2 is a 101-residue molecule with two predicted transmembrane domains. Topology models predict that the N- and C-termini are cytosolic, which places the small loop between the transmembrane domains in the extracellular side, and this is the way most people draw pen2 on their slides. The probability that this prediction is true, given by the TMHMM algorithm (see related Web site), is 78 percent. However, Doms et al. now show experimentally, by introducing artificial N-glycosylation sites, that the topology is likely just the other way around: The loop is cytosolic, and the termini are in the lumen of the ER. This result is obviously of interest for a model of the complete γ-secretase complex, and it shows that bioinformatic predictions should be taken with a grain of salt.

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