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As several other \u03b3\u2010secretase substrates including Notch1 and <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>44 have crucial signaling functions, an understanding of the mechanism of substrate recognition and cleavage is key for the development of <jats:styled-content style=\"fixed-case\">APP<\/jats:styled-content> selective \u03b3\u2010secretase\u2010targeting drugs. The \u03b3\u2010secretase active site domain in its catalytic subunit presenilin (<jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>) 1 has been implicated in substrate recognition\/docking and cleavage. Highly critical in this process is its Gx<jats:styled-content style=\"fixed-case\">GD<\/jats:styled-content> active site motif, whose invariant glycine residues cannot be replaced without causing severe functional losses in substrate selection and\/or cleavage efficiency. Here, we have investigated the contribution of the less well characterized residue x of the motif (L383 in <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1) to this function. Extensive mutational analysis showed that processing of <jats:styled-content style=\"fixed-case\">APP<\/jats:styled-content> was overall well\u2010tolerated over a wide range of hydrophobic and hydrophilic mutations. Interestingly, however, most L383 mutants gave rise to reduced levels of A\u03b2<jats:sub>37\u201339<\/jats:sub> species, and several increased the pathogenic A\u03b2<jats:sub>42\/43<\/jats:sub> species. Several of the A\u03b2<jats:sub>42\/43<\/jats:sub>\u2010increasing mutants severely impaired the cleavages of Notch1 and <jats:styled-content style=\"fixed-case\">CD<\/jats:styled-content>44 substrates, which were not affected by any other L383 mutation. Our data thus establish an important, but compared with the glycine residues of the motif, overall less critical functional role for L383. We suggest that L383 and the flanking glycine residues form a spatial arrangement in <jats:styled-content style=\"fixed-case\">PS<\/jats:styled-content>1 that is critical for docking and\/or cleavage of different \u03b3\u2010secretase substrates.<\/jats:p>","DOI":"10.1111\/jnc.12124","type":"journal-article","created":{"date-parts":[[2012,12,13]],"date-time":"2012-12-13T17:22:20Z","timestamp":1355419340000},"page":"144-156","source":"Crossref","is-referenced-by-count":18,"title":["Important functional role of residue x of the presenilin Gx<scp>GD<\/scp> protease active site motif for <scp>APP<\/scp> substrate cleavage specificity and substrate selectivity of \u03b3\u2010secretase"],"prefix":"10.1111","volume":"125","author":[{"given":"Benedikt","family":"Kretner","sequence":"first","affiliation":[{"name":"Adolf\u2010Butenandt\u2010Institute Biochemistry Ludwig\u2010Maximilians\u2010University Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Fukumori","sequence":"additional","affiliation":[{"name":"Adolf\u2010Butenandt\u2010Institute Biochemistry Ludwig\u2010Maximilians\u2010University Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peer\u2010Hendrik","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Adolf\u2010Butenandt\u2010Institute Biochemistry Ludwig\u2010Maximilians\u2010University Munich Germany"},{"name":"DZNE German Center for Neurodegenerative Diseases Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca Isabel","family":"P\u00e9rez\u2010Revuelta","sequence":"additional","affiliation":[{"name":"Adolf\u2010Butenandt\u2010Institute Biochemistry Ludwig\u2010Maximilians\u2010University Munich Germany"},{"name":"DZNE German Center for Neurodegenerative Diseases Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan 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