The PERK pathway Sample Clauses

The PERK pathway. PERK is a type I ER resident transmembrane protein which under normal conditions is kept inactive by binding BiP/GRP78 (Xxxxxxxxxx et al., 2000; Xxxxxx and Xxx, 2011). The N-terminal luminal domain functions as a stress sensor whereas the C-terminal cytosolic domain has serine/threonine kinase activity (Xxxxxxx et al., 1999). Upon dissociation of BiP/GRP78 in the presence of unfolded proteins, PERK undergoes dimerisation and autophosphorylation (Xxxxxxxxxx et al., 2000; Xxxxxx and Xxx, 2011). Active PERK phosphorylates eIF2α which inhibits the formation of the 43S translation initiation complex (Xxxxxxx et al., 1999; Xxxxx et al., 2006) and consequently attenuates protein translation (Xxxxx et al., 2013). Although phosphorylation of eIF2α inhibits translation in general it increases the translation of activating transcription factor 4 (ATF4) (Xxxxxxx et al., 2000). ATF4 is essential for the upregulation of UPR associated genes with functions in amino acid metabolism, redox homeostasis and apoptosis (Xxxxxxx et al., 2003; Xxxxx and Xxxxxx, 2008). Another substrate of PERK is Nrf2, a cytoplasmic protein that is phosphorylated under ER stress conditions and activates the transcription of genes encoding detoxifying proteins (Xxxxxxxx and Xxxxx, 2006). PERK is dephosphorylated and thereby inactivated after protein homeostasis is restored within the ER (Xxxxxxxxxx et al., 2000).