Assembly of the MHC I peptide-loading complex determined by a conserved ionic lock-switch

Abstract

Salt bridges in lipid bilayers play a decisive role in the dynamic assembly and downstream signaling of the natural killer and T-cell receptors. Here, we describe the identification of an inter-subunit salt bridge in the membrane within yet another key component of the immune system, the peptide-loading complex (PLC). The PLC regulates cell surface presentation of self-antigens and antigenic peptides via molecules of the major histocompatibility complex class I. We demonstrate that a single salt bridge in the membrane between the transporter associated with antigen processing TAP and the MHC I-specific chaperone tapasin is essential for the assembly of the PLC and for efficient MHC I antigen presentation. Molecular modeling and all-atom molecular dynamics simulations suggest an ionic lock-switch mechanism for the binding of TAP to tapasin, in which an unfavorable uncompensated charge in the ER-membrane is prevented through complex formation. Our findings not only deepen the understanding of the interaction network within the PLC, but also provide evidence for a general interaction principle of dynamic multiprotein membrane complexes in immunity.

Crystal structure and mechanistic basis of a functional homolog of the antigen transporter TAP

“…We transfected the TAP1-deficient cells with TmrA and TmrB containing the extra domain TMD0 of TAP2 for the interaction with components of the MHC-I peptide-loading complex (Fig. 3A) (15,21,22). As expected, coreTAP1 (lacking its TMD0) can restore antigen processing by pairing with the endogenous TAP2 in TAP1-deficient cells, as evidenced by a significant increase in MHC-I surface expression ( Fig.…”

TAPBPR Promotes Antigen Loading on MHC-I Molecules Using a Peptide Trap

“…Local peptide concentrations will be highest in the vicinity of the TAP transporter, which acts as a hub around which PLC components associate. Tapasin lacks a long loop, but is tethered to the TAP transporter using a conserved Lys/Asp transmembrane salt-bridge (36) and therefore can still load cognate peptide ligands efficiently due to the increased local concentration (Fig. 6C) .…”

PAKC: A novel Panel of HLA class I Antigen presentation machinery Knockout Cells from the same genetic origin

“…The regulation of tapasin homeostasis and the functional consequences thereof are still unknown. In the opposite direction, tapasin has been described to stabilize TAP, showing the complexity of peptide loading complex regulation(23). These findings demonstrate that PAKC provides opportunities to understand the interplay between different APM components.…”