InterPro domain: IPR001193

This entry represents the membrane-bound transcription factor site-2 protease (MBTPS2, also known as S2P) [ 1 ].

MBTPS2 is a membrane-embedded zinc metalloprotease that activates signaling proteins involved in sterol control of transcription and ER stress response [ 2 ]. It cleaves several transcription factors that are type-2 transmembrane proteins within membrane-spanning domains. Its known substrates include sterol regulatory element-binding protein (SREBP) -1, SREBP-2 and forms of the transcriptional activator ATF6 [ 2 , 3 ].

Mutations in the MBTPS2 gene cause IFAP syndrome with or without BRESHECK syndrome (IFAPS) and Keratosis follicularis spinulosa decalvans X-linked (KFSDX) [ 4 , 4 ].

S2Ps are widely distributed in bacteria and participate in diverse pathways that control functions such as membrane integrity, sporulation, lipid biosynthesis, pheromone production, virulence, and others [ 5 ].

1. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am. J. Hum. Genet. 84, 459-67
2. Complementation cloning of S2P, a gene encoding a putative metalloprotease required for intramembrane cleavage of SREBPs. Mol. Cell 1, 47-57
3. Membrane topology of S2P, a protein required for intramembranous cleavage of sterol regulatory element-binding proteins. J. Biol. Chem. 274, 21973-80
4. Keratosis Follicularis Spinulosa Decalvans is caused by mutations in MBTPS2. Hum. Mutat. 31, 1125-33
5. Function of site-2 proteases in bacteria and bacterial pathogens. Biochim. Biophys. Acta 1828, 2808-14