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Abstract
The MILL family, composed of MILL1 and MILL2, is a group of nonclassical MHC class I molecules that occur in some orders of mammals. It has been reported that mouse MILL2 is involved in wound healing; however, the molecular mechanisms remain unknown. Here, we determine the crystal structure of MILL2 at 2.15 Å resolution, revealing an organization similar to classical MHC class I. However, the α1-α2 domains are not tightly fixed on the α3-β2m domains, indicating unusual interdomain flexibility. The groove between the two helices in the α1-α2 domains is too narrow to permit ligand binding. Notably, an unusual basic patch on the α3 domain is involved in the binding to heparan sulfate which is essential for MILL2 interactions with fibroblasts. These findings suggest that MILL2 has a unique structural architecture and physiological role, with binding to heparan sulfate proteoglycans on fibroblasts possibly regulating cellular recruitment in biological events.
Highlights
The MILL family, composed of MILL1 and MILL2, is a group of nonclassical MHC class I molecules that occur in some orders of mammals
We identified a nonclassical major histocompatibility complex class I (MHC-I) gene family designated as MILL (MHC-I-like located near the leukocyte receptor complex) in the genomes of rodents[19,20], marsupials[21] and odd-toed ungulates[20]
Based on the MILL2 tetramer-staining assay, we show that this basic patch in the α3 domain forms a binding site for heparan sulfate (HS) on the surface of NIH-3T3 cells, indicating that heparan sulfate proteoglycans (HSPGs) on fibroblasts may be physiological ligands for MILL2
Summary
The MILL family, composed of MILL1 and MILL2, is a group of nonclassical MHC class I molecules that occur in some orders of mammals. During CD8+ cytotoxic T cell activation, the CD8 co-receptor can enhance interactions with classical MHC-I by binding to the α3 domain[4,5]. Based on the MILL2 tetramer-staining assay, we show that this basic patch in the α3 domain forms a binding site for heparan sulfate (HS) on the surface of NIH-3T3 cells, indicating that heparan sulfate proteoglycans (HSPGs) on fibroblasts may be physiological ligands for MILL2.
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