Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

Area of Science:

• Immunology
• Structural Biology
• Biochemistry

Background:

• Endoplasmic reticulum (ER) aminopeptidases are crucial for generating peptides presented by MHC class I molecules.
• These enzymes shape the T-cell response by processing a wide array of peptide sequences.
• Understanding substrate recognition mechanisms is key to elucidating ER aminopeptidase function.

Purpose of the Study:

• To elucidate the substrate recognition mechanism of ER aminopeptidase 2 (ERAP2).
• To understand how ERAP2 processes diverse peptide sequences for MHC class I presentation.

Main Methods:

• Determined crystal structures of ERAP2 in complex with a substrate analogue and a peptidic product.
• Compared complex structures with the apo-form structure of ERAP2.
• Performed enzymatic analyses to assess the impact of observed interactions on trimming rates.

Main Results:

• Peptides were localized within ERAP2's internal cavity, inaccessible to the solvent.
• Substrate analogue and product engaged with shallow pockets, indicating opportunistic interactions.
• Enzymatic assays confirmed that these interactions influence peptide trimming rates.
• ERAP2 lacks deep specificity pockets and specific C-terminal recognition, unlike ERAP1.

Conclusions:

• ERAP2 employs a limited-selectivity model for antigenic peptide processing.
• Substrate selection involves sequestration within the enzyme's internal cavity and opportunistic interactions.
• This mechanism allows ERAP2 to be permissive to various substrates while maintaining sequence bias.
• Functional differences between ERAP2 and ERAP1 stem from distinct substrate recognition strategies.