Abstract
Neurons in the murine vomeronasal organ (VNO) express a family of class Ib major histocompatibility complex (MHC) proteins (M10s) that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide–binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I–binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8–10-mer class I–binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC–binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs.
Highlights
In most mammals, chemical communication between conspecific animals is involved in initiation of reproductive and territorial behaviors
Mouse pheromone receptors can be divided into two subtypes, V1R and V2R, each of which is expressed in the dendritic tips of bipolar neurons in spatially distinct regions of the vomeronasal organ (VNO)
The role of M10 molecules in V2R signaling is unclear, direct homologs of proteins typically associated with immunogenic identity such as major histocompatibility complex (MHC) proteins provide attractive candidates to mediate MHC–disassortative mating preferences [17] and pregnancyblock phenomena [18]
Summary
Chemical communication between conspecific animals is involved in initiation of reproductive and territorial behaviors. The detection of these species- and gender-specific chemical cues, called pheromones, is thought to involve receptors of the vomeronasal organ (VNO), a small neuronal epithelium located between the nasal cavity and the palate [1]. Pheromone receptors belong to the ubiquitous family of G protein–coupled receptors (GPCRs), but are unrelated in sequence to main olfactory epithelium receptors that detect volatile odorants [4,5]. Mouse V1R receptors are found in the apical VNO domain, are thought to signal through the G-protein a-subunit Gai, and exhibit sequence similarity to the T2R family of bitter taste receptors [6]. V1R and V2R receptor family members, like all G protein–coupled receptors, contain seven putative transmembrane helices, but, in addition, V2R members include a large N-terminal extracellular domain
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