ASKEW Flashcards
The accumulation of unfolded proteins in the ER creates unfolded protein __________, activating a cellular stress response pathway called the __________.
stress, unfolded protein response (UPR)
The entry point for most proteins destined for the cell surface or secretion is the __________. This organelle handles up to a __________ (fractional amount) of the cellular proteome.
ER, third
Three mechanisms within the ER assist in the proper folding of proteins: __________, __________, and __________.
Chaperones, folding enzymes, N-linked glycosylation
___________ associate with newly formed peptides, preventing improper interactions and stabilizing partially unfolded proteins.
Chaperones
__________ catalyze the formation of disulfide bonds, frequently found in secreted proteins, while __________ accelerate the isomerization of proline peptide bonds, facilitating protein folding.
Protein disulfide isomerases; peptidyl prolyl isomerases
In __________, a common oligosaccharide, synthesized on a lipid carrier in the ER membrane, is transferred to a growing polypeptide and subsequently trimmed in the __________ and __________ to aid in protein folding.
N-linked glycosylation; ER; Golgi
The __________ is a 22 base pair DNA sequence found in the promoter region of genes involved in the unfolded protein response, and it was identified in __________.
UPRE (unfolded protein response element); 1992
__________, a type I transmembrane protein with a kinase domain, was identified as the ER stress sensor in yeast using a genetic screen based on a __________.
Ire1; UPRE-reporter
In yeast, the __________ transcription factor, encoded by a splice variant, plays a critical role in regulating the UPR.
Hac1
Ire1 possesses an __________ domain in its cytosolic N-terminal region and is responsible for splicing the __________ mRNA to generate the active __________ mRNA, ultimately leading to the production of the functional Hac1 transcription factor.
RNAse-like; HAC1u; HAC1i
The two models proposed for Ire1 activation are the __________ and the __________.
Direct binding model; chaperone inhibition model
The mammalian UPR consists of three branches, including the conserved __________ pathway and two additional branches: __________ and __________.
IRE1; ATF6; PERK
The __________ sensor is an ER transmembrane protein that, upon ER stress, translocates to the Golgi and undergoes cleavage by proteases, releasing its cytosolic transcription factor domain.
ATF6
The __________ sensor, an ER transmembrane protein with a cytosolic eIF2α kinase domain, alleviates ER stress by phosphorylating __________, leading to global translational repression while simultaneously enabling the translation of specific transcription factors like __________.
PERK; eIF2α; ATF4
__________, a process that eliminates terminally misfolded proteins from the ER through ubiquitination and proteasomal degradation, plays a crucial role in mitigating ER stress.
ERAD (ER-associated degradation)
When the UPR fails to restore homeostasis, prolonged ER stress triggers the activation of __________, a key transcription factor involved in apoptosis.
CHOP
Pharmacologic manipulation of UPR-mediated apoptotic pathways offers promising therapeutic strategies for treating __________ and __________.
Cancer; infections caused by intracellular microbes
Inhibiting the UPR in __________ can induce toxic levels of unfolded proteins and trigger apoptosis, while suppressing UPR-mediated apoptosis in __________ may offer protection against cell loss associated with protein misfolding.
Cancer cells; neurodegenerative diseases
The historical perspective of the UPR highlights how the field evolved from studying RNA tumor viruses, specifically __________, to investigating the protein __________, which was initially found to be induced by glucose starvation.
RSV (Rous sarcoma virus), GRP78 (glucose-regulated protein 78)
GRP78 was later identified as __________, an ER chaperone known to interact with immunoglobulin heavy chains in B cells.
BiP (binding immunoglobulin protein)
Scientists observed that __________, __________, and __________ all induce GRP78 expression, suggesting a common underlying mechanism related to protein folding stress in the ER.
Glucose starvation, glycosylation inhibitors, toxic amino acid analogues
The yeast homolog of GRP78/BiP is called __________, and its gene, __________, was found to be induced by ER stress, paving the way for further investigation into the UPR in yeast.
Kar2p, KAR2
Researchers utilized a yeast mutant, __________, that is temperature-sensitive for N-glycosylation to screen for mutants defective in UPR signaling, ultimately leading to the identification of the gene __________.
Sec53, Ire1
The discovery that the intron in the __________ mRNA lacks consensus splicing sites and that Ire1’s RNAse domain is cytoplasmic suggested an unconventional splicing mechanism.
HAC1
The crystal structure of Ire1, with its symmetrical dimer and a groove resembling the peptide-binding groove of __________, provided support for the direct binding model of Ire1 activation.
MHC (major histocompatibility complex) complexes
___________, an ER chaperone, plays a key role in both the direct binding and chaperone inhibition models of Ire1 activation.
BiP
The mammalian UPR exhibits two additional branches, absent in yeast, that contribute to relieving ER stress: the __________ sensor and the __________ sensor.
ATF6, PERK
In the mammalian UPR, the __________ pathway is conserved and involves the splicing of the __________ mRNA to produce the active transcription factor that regulates the expression of UPR target genes.
IRE1, XBP1u
The __________ is an adaptive stress response pathway activated by cells to cope with unfolded protein stress.
Unfolded protein response (UPR)
The enzyme __________ catalyzes the formation of disulfide bonds between cysteine residues.
protein disulfide isomerase
___________ is the enzyme that catalyzes the isomerization of proline peptide bonds.
Peptidyl prolyl isomerase
The UPR involves signal transduction across the ER membrane to communicate ER stress to the __________.
nucleus
Unfolded proteins can cause various problems for the cell, including __________, __________, __________, and __________.
Loss of function; proteome imbalance; illegitimate interactions; energetic cost of repair
In mammalian cells, ___________ is a transcription factor activated by all three UPR pathways and is a key mediator of apoptosis in response to unresolved ER stress.
CHOP
In the chaperone inhibition model, ___________ binding to Ire1 keeps the sensor monomeric and inactive.
BiP
