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Antigen Processing Pathways

Antigen Processing Pathways

MHC molecules are key players in the immune response, enabling T cells to recognize and respond to specific antigens. They are present on the surface of all nucleated cells in the body and are instrumental in presenting antigens to T cells and activating them. T cells recognize the MHC-antigen complex and initiate an immune response. MHC class I and MHC class II are two main types of MHC molecules, each associated with a distinct antigen processing pathway.
MHC Class I: Presenting Endogenous...

Directing Proteins to the Rough Endoplasmic Reticulum

Directing Proteins to the Rough Endoplasmic Reticulum

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...

Export of Misfolded Proteins out of the ER

Export of Misfolded Proteins out of the ER

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...

Protein Folding Quality Check in the RER

Protein Folding Quality Check in the RER

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...

Protein Modifications in the RER

Protein Modifications in the RER

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.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal sequences.

ER Retrieval Pathway

ER Retrieval Pathway

In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...

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Purification of the Membrane Compartment for Endoplasmic Reticulum-associated Degradation of Exogenous Antigens in Cross-presentation

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Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1.

Tina T Nguyen¹, Shih-Chung Chang, Irini Evnouchidou

¹Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

Nature Structural & Molecular Biology

|April 12, 2011

Summary

The enzyme ERAP1 trims long peptides for MHC class I presentation. Its unique structure explains how it selectively shortens antigens, a key step in immune response.

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Area of Science:

Structural biology
Immunology
Biochemistry

Background:

Endoplasmic reticulum-associated aminopeptidase 1 (ERAP1) is crucial for processing antigenic peptides.
ERAP1 exhibits unique substrate preferences, trimming long peptides while sparing shorter ones.
Understanding ERAP1's structural basis is key to elucidating its specialized function in antigen presentation.

Purpose of the Study:

To determine the X-ray crystal structure of human ERAP1 bound to bestatin.
To identify the structural features responsible for ERAP1's length-dependent trimming activity.
To elucidate the mechanism underlying ERAP1's substrate specificity for antigenic peptide precursors.

Main Methods:

X-ray crystallography of human ERAP1 in complex with bestatin.
Structural analysis of the enzyme's active site and substrate-binding groove.
Biochemical assays to investigate length-dependent trimming activity.

Main Results:

The crystal structure revealed an open conformation of ERAP1 with a large internal compartment.
An extended groove accommodates long peptides, explaining ERAP1's broad specificity.
Binding of long substrates induces a conformational change, reorienting a catalytic residue.

Conclusions:

ERAP1's unique structural elements facilitate the trimming of antigenic peptide precursors.
A conformational change mechanism explains ERAP1's length-dependent trimming activity.
ERAP1 represents an adaptation of a generic aminopeptidase for specialized immune functions.