HLA-E (human leukocyte antigen E) in complex with VL9 peptide (HLA-E/VL9 complex)

HLA-E is a non-polymorphic non-classical MHC class I molecule that primarily binds and presents the conserved nonameric VL9 peptide (VMAPRT[V/L][L/V/I/F]L, typically VMAPRTVLL or variants) derived from leader sequences of classical MHC class Ia molecules (HLA-A, HLA-B, HLA-C, HLA-G). This complex is expressed on cell surfaces to signal integrity of the MHC Ia presentation pathway, engaging CD94/NKG2 receptors on natural killer (NK) cells: inhibitory NKG2A/CD94 to prevent lysis of healthy cells, or activating NKG2C/CD94. VL9 binding stabilizes HLA-E folding, promotes ER export and surface expression, occupies multiple pockets (B, D, C, E, F) in the peptide-binding groove, and results in a compact, rigid conformation recognized specifically by NKG2A/CD94. Pathogen-derived or low-affinity peptides bind less stably, forming heterogeneous ensembles with disrupted E-pocket interactions and α2 helix reconfiguration (e.g., at E152), altering immune recognition landscapes for T-cell or Stabilin receptor discrimination. Limited polymorphism (e.g., HLA-E*01:01 vs *01:03 differing at position 107) preserves VL9 presentation. The complex regulates NK cell "missing self" surveillance, with therapeutic potential via antibodies like 3H4 that block receptor docking to boost anti-tumor/infection NK activity.

Other names

HLA-E-VL9MHC-E/VL9HLA-E bound to VL9

Drugs targeting HLA-E/VL9 complex act by blocking CD94/NKG2A docking to enhance NK cell killing, preventing the NKG2A/CD94 interaction with HLA-E-VL9, thereby enhancing NK cell-mediated cytotoxicity against HLA-E-VL9-expressing cells.