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Directing Proteins to the Rough Endoplasmic Reticulum01:34

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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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ERAP1-ERAP2 dimerization increases peptide-trimming efficiency.

Irini Evnouchidou1, Mirjana Weimershaus1, Loredana Saveanu1

  • 1INSERM Unité 1151, 75015 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8253, 75015 Paris, France; and Faculté de Medicine, Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France.

Journal of Immunology (Baltimore, Md. : 1950)
|June 15, 2014
PubMed
Summary
This summary is machine-generated.

Endoplasmic reticulum aminopeptidases (ERAP)1 and ERAP2 form heterodimers that efficiently trim peptides for MHC class I presentation. This ERAP1-ERAP2 complex enhances antigen presentation more effectively than individual enzymes.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Protein Biochemistry

Background:

  • Endoplasmic reticulum aminopeptidases (ERAP)1 and ERAP2 are crucial for generating antigenic peptides presented by MHC class I molecules.
  • Heterodimerization between ERAP1 and ERAP2 is hypothesized to enhance peptide trimming, but its functional impact is not well understood.

Purpose of the Study:

  • To investigate the functional consequences of ERAP1-ERAP2 heterodimerization on peptide processing and antigen presentation.
  • To characterize the enzymatic properties of stabilized ERAP1-ERAP2 heterodimers.

Main Methods:

  • Production of stabilized ERAP1-ERAP2 heterodimers.
  • Enzymatic assays to compare the peptide-trimming efficiency of heterodimers versus a mixture of individual enzymes.
  • Analysis of changes in ERAP1 enzymatic parameters upon interaction with ERAP2.

Main Results:

  • Stabilized ERAP1-ERAP2 heterodimers exhibited superior efficiency in producing mature epitopes compared to non-dimerized enzyme mixtures.
  • ERAP2 binding altered ERAP1's basic enzymatic parameters, notably enhancing its substrate-binding affinity.
  • Dimerization brings ERAP1 and ERAP2 into proximity and induces allosteric effects, leading to enhanced peptide-trimming efficacy.

Conclusions:

  • ERAP1-ERAP2 heterodimerization creates a complex with significantly improved peptide-trimming capabilities.
  • These heterodimeric complexes are likely to play a key role in enhancing antigen presentation in cells co-expressing ERAP1 and ERAP2.