Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation

Related Experiment Video

Updated: Oct 21, 2025

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
15:05

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Published on: May 20, 2020

8.9K

Zachary Maben1, Richa Arya1, Dimitris Georgiadis2

  • 1Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.

Nature Communications
|September 7, 2021
PubMed

Insights

Endoplasmic-reticulum aminopeptidase ERAP1 undergoes conformational changes in solution, crucial for its catalytic function in antigen processing. These dynamics explain allosteric regulation and disease associations.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Immunology

Background:

  • Endoplasmic-reticulum aminopeptidase 1 (ERAP1) is essential for antigen presentation via MHC-I.
  • ERAP1 processes antigenic peptides for CD8 T cell recognition during immune surveillance.
  • Previous studies showed ERAP1 exists in open or closed conformations, but their in-solution relevance was unclear.

Purpose of the Study:

  • To investigate ERAP1 conformational states in solution.
  • To determine the role of these states in ERAP1 catalysis and regulation.

Main Methods:

  • Small-angle X-ray scattering (SAXS) to assess solution conformations.
  • X-ray crystallography to characterize protein structural changes.
  • Chemical crosslinking to identify alternate binding sites.

Main Results:

  • ERAP1 conformational states in solution were identified in the presence of substrates, activators, and inhibitors.
  • Structural reconfigurations of the ERAP1 active site are linked to domain closure.
  • Binding of long peptide substrates promotes these domain closures and active site changes.

Conclusions:

  • ERAP1 conformational dynamics are integral to its catalytic cycle.
  • These dynamics provide a mechanism for allosteric regulation of ERAP1.
  • The findings offer insight into disease associations linked to ERAP1 polymorphisms.

More Related Videos

Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation08:00

Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation

Published on: October 4, 2024

781
Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET10:59

Visualizing the Conformational Dynamics of Membrane Receptors Using Single-Molecule FRET

Published on: August 17, 2022

3.4K

Related Concept Videos

Allosteric Regulation01:08

Allosteric Regulation

Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
61.3K
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

2.5K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

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...
2.7K
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
6.0K
The Unfolded Protein Response01:37

The Unfolded Protein Response

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...
5.4K
Directing Proteins to the Rough Endoplasmic Reticulum01:34

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...
13.1K