Survey
* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project
Download Document
Document related concepts
no text concepts found
Transcript
Translation initiation factor eIF2: Initiation and Recycling Phosphorylation of eIF2a reduces the concentration of the eIF2-GTP-tRNAMet eIF2-GTP-tRNAMet Ternary eIF2 Complex b a GTP GTP g tRNAMet 40S 40S eIF2B eIF2a kinase GTP PO3 GDP tRNAMet 40S GTP 5’cap tRNAMet 40S GTP tRNAMet 40S GTP tRNAMet AUG 60S 40S 60S High concentration of eIF2-GTP-tRNAMet GDP GTP Repressed translation GDP 40S 40S 40S 40S GTP 60SuORF 60S GTP 40S GTP GCN4 60SuORF 60S Low concentration of eIF2-GTP-tRNAMet GDP 40S GTP GTP 60SuORF 40S 40S uORF 40S GTP GDP 40S GTP Derepressed translation GCN4 40S 60S 60S Selection of alternative in-frame start codons are sensitive to eIF2 alpha phosphorylation AUG AUG eIF2a kinases Heme deprivation (disassociation of hemin) Amino acid deprivation (binding uncharged tRNAs) Calcium mobilization or misfolded proteins (disassociation of BiP-GRP78) GCN2 Viral infection (binding dsRNA) HRI PERK PKR PO3 b (-) Initiation of protein synthesis a NRF-2 g eIF2 Transcription (+) mRNA specific translation initiation Activation of PERK via ER stress and loss of ER calcium Endoplasmic reticulum Thapsigargin SERCA BiP Ca2+ = 5x10-5M RyR Ca2+ IP3R ATP Inactive Activated PERK PERK Repression of global Adaptation to protein synthesis stress or apoptosis (e.g. activation ATF-4 -> CHOP) Receptor-mediated generation of IP3 and/or activation of voltage-gated channels stimulates ER calcium mobilization Ligand and activation of PERK Ca2+ GCPR Endoplasmic reticulum SERCA BiP Ca2+ = 5x10-5M IP3 IP3R Ca2+ RyR Ca2+ ATP Inactive Activated PERK PERK Glucose metabolism increases ER calcium and represses PERK glucose .... ... .... exocytosis VGCC K+ATP GLUT2 PMCA plasma membrane Ca2+ Ca2+ (10-7M) K+ Ca2+ IP3R ATP Secreted proteins Secretory machinery Differentiation factors Proliferatiaon factors SERCA ER BiP Ca2+ (5x10-5M) nucleus Transcription factors Inactive PERK Activated dimerized PERK Translation control of specific mRNAs Glucose metabolism generating driving transient ATP and calcium-induced driving sustainted calcium release from Calcium uptake the in ERthe ER by the SERCA calcium pump ATPase Glucose Ca2+ ATP ATP Endoplasmic reticulum SERCA BiP Ca2+ Ca2+ RyR Ca2+ RYR Ca2+ ATP Inactive Activated PERK PERK Extracellular physiological, developmental, and stress signals PERK sensor Protein synthesis Intracellular signals ER signals ER Translation of specific genes Reduction of co-translational import nucleus Modulation of secretory capacity: maintenance of differentiated state, cell mass, secretory machinery PERK regulates a continuum of normal developmental and ER stress related processes Normal developmental and physiological modulation of ER activity regulates PERK activity which in turn activates/represses genes that modulate normal growth and development. ER stress hyperactivates PERK leading to the activation of stress response genes. Thus, the degree to which PERK is activated determines which particular subset of regulatory circuits are activated or repressed.
Related documents