Structural Biochemistry/Unfolded Protein Response
Modulating Stress by UPRosome
The buildup of unfolded proteins in the endoplasmic reticulum (ER) activate sensors like inositol-requiring enzyme-1α (IRE1α). These activated sensors carry out the unfolded protein response (UPR) by creating a protein platform called the UPRosome. The speed and strength of the the UPR responses are regulated by a group of modulator and adaptor proteins. Stress to the ER can cause apoptosis (programmed cell death), but some of the apoptotic proteins will interact with IRE1α. This interaction will have two functions: one to regulate apoptosis and one that adapts to stress.
The ER oversees the quality of protein folding; inside the ER lumen, protein chaperones, foldases, and cofactors to make sure that these proteins fold correctly. The proteins that are correctly folded will then be sent to their respective places in the body through vesicular transport, but stress will impair the ER. Under stressful conditions the protein homeostasis will be thrown off balance, which causes a buildup of misfolded proteins called ER stress. The unfolded protein response (UPR)is a set of intracellular signaling pathways that regulate the folding process. The UPR uses UPR transductase to increase the number of proteins that are involved in the regulation such as folding proteins, quality control, and ER-associated degradation (ERAD), which helps restore the protein homeostasis by changing the ER's ability to fold and remove incorrectly folded proteins. If the homeostasis cannot be rebalanced, the UPR triggers apoptosis or programmed cell death to get rid of damaged cells. 
Many neurodegenerative diseases like Alzheimer's, Parkinson's and amyotrophic lateral sclerosis (ALS) are caused by abnormally folded proteins, which is a result of severe ER stress. Proteins in these diseases makes unusual aggregations, which lead to the disease. 
UPR Activation and Stress Sensors
There are three UPR stress sensors: i) inositol requiring enzyme 1α; ii) protein kinases RNA-activated (PKr)-like ER kinase (PERK); and iii) activating transcription factor 6 (ATF6). They control the expression of certain transcription factors by conveying information to the nucleus of the cell.
Hetz and Wohlbier state that the IRE1α is a type I transmembrane protein that has a RNase domain, a cytosolic kinase domain, an N terminal in the luminal region. These proteins in their activated form will want to create oligomeric complexes in order to trans-autophosphorylate themselves.There are two models that have been suggests to explain how the activation of IRE1α occurs and how it senses stress. The first model asserts that the immunoglobulin-binding protein (BiP) binds to IRE1α to inhibit oligomerization of IRE1α. The buildup of unfolded proteins makes the BiP dissociate with the IRE1α so that BiP can interact with the unfolded proteins. When BiP and IRE1α separate the IRE1α is now free to interact with itself, which causes a spontaneous formation of IRE1α oligomeric complexes. The second model suggests that the unfolded protein induce the creation of these IRE1α complexes by directly interacting with the protein's luminal domain.
PERK is also a type I transmembrane protein that has a cytosolic kinase domain and a N-terminal in the luminal region. It is proposed that the mechanism for PERK is similar to the mechanism for IRE1α. Activated PERK can cause reduce the overproduction of proteins in the ER and upregulate genes that will help restore protein homeostasis during times of ER stress by phosphorylating the eukaryotic translation initiation factor 2α (eIF2α).
Unlike IRE1α and PERK, ATF6 is a type II transmembrane protein. This proteins like to bind to BiP under basic conditions, but the buildup of unfolded proteins will cause them to separate because the BiP wants to bind to the unfolded proteins. When they separate disulfide bond in the ATF6 will be reduced, which caused the a fragment of the protein to be able to go the nucleus of the cell to increase the transciption of ER chaperones and ERAD.