Atomistic structure and dynamics of the human MHC-I peptide-loading complex

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• The major histocompatibility complex class-I (MHC-I) peptide-loading complex (PLC) is crucial for adaptive immunity.
• It presents antigens to killer T cells, distinguishing healthy from compromised cells.

Purpose of the Study:

• To create an atomistic model of the PLC based on cryo-EM data.
• To investigate the conformational dynamics of the PLC using molecular dynamics simulations.

Main Methods:

• Developed an atomistic model of the PLC.
• Performed all-atom molecular dynamics (MD) simulations in an explicit lipid bilayer and water environment.
• Analyzed multimicrosecond conformational dynamics.

Main Results:

• The PLC exhibits a layered structure with flexible editing modules and a stable core.
• Tapasin stabilizes the MHC-I binding groove.
• MHC-I-linked glycan influences a tapasin loop involved in peptide editing.
• Calreticulin affects tapasin dynamics, facilitating MHC-I recruitment.

Conclusions:

• The study provides a detailed atomistic view of the PLC.
• Conformational dynamics are key to the PLC's function in antigen presentation.
• Tapasin and calreticulin play critical roles in MHC-I loading and immune surveillance.