Comparative study of the molecular variation between ‘central’ and ‘peripheral’ MUPs and significance for behavioural signalling

Abstract

MUPs (major urinary proteins) play an important role in chemical signalling in rodents and possibly other animals. In the house mouse (Mus musculus domesticus) MUPs in urine and other bodily fluids trigger a range of behavioural responses that are only partially understood. There are at least 21 Mup genes in the C57BL/6 mouse genome, all located on chromosome 4, encoding sequences of high similarity. Further analysis separates the MUPs into two groups, the 'central' near-identical MUPs with over 97% sequence identity and the 'peripheral' MUPs with a greater degree of heterogeneity and approximately 20-30% non-conserved amino acids. This review focuses on differences between the two MUP sub-groups and categorizes these changes in terms of molecular structure and pheromone binding. As small differences in amino acid sequence can result in marked changes in behavioural response to the signal, we explore the potential of single amino acid changes to affect chemical signalling and protein stabilization. Using analysis of existing molecular structures available in the PDB we compare the chemical and physical properties of the ligand cavities between the MUPs. Furthermore, we identify differences on the solvent exposed surfaces of the proteins, which are characteristic of protein-protein interaction sites. Correlations can be seen between molecular heterogeneity and the specialized roles attributed to some MUPs.

Diversity of major urinary proteins (MUPs) in wild house mice

“…The genetic analyses detected some sequence variation in Mup genes and promoters, but no measures of individual variation were reported and no comparisons with other loci were made. The results confirmed that different Mup loci are highly homologous9 and provided evidence that they are under purifying selection, which is consistent with our findings. The proteomic analysis examined variation and consistency in individual urine protein profiles, as we previously conducted14, though they used a top-down, ESI/MS approach, in which MUPs were classified by the mass of intact proteins.…”

“…In house mice, MUPs are encoded by 21 paralogous genes (and at least 20 pseudogenes) inside a 2 Mb cluster on chromosome 478. Mup genes show very high sequence similarity among loci89, which makes it difficult to understand how these genes could also be highly polymorphic.…”

Molecular heterogeneity in major urinary proteins of Mus musculus subspecies: potential candidates involved in speciation

“…The cavity residues of central MUPs are highly conserved, with only one out of 20 residues showing variation. This involves either a valine or phenylalanine variation at residue number 56, located at the base of the central cavity49. The dominant isoforms that differed between musculus and domesticus MUP profiles in the contact zone appear largely to concern MUP surface rather than cavity residues, with the dominant MUPs in both subspecies sharing a valine residue at cavity position 56.…”

“…Although MUPs are expressed in different tissues, the predominant route of expression for most MUPs is synthesis in the liver, followed by passage through the glomerular filter and excretion in urine. The MUPs are eight stranded beta barrel structures enclosing a well-defined cavity that can bind and effect a slow release of volatile pheromones2846474849. There is also a growing body of evidence that MUPs act as signalling molecules in their own right.…”

Mouse Lipocalins (MUP, OBP, LCN) Are Co-expressed in Tissues Involved in Chemical Communication

“…Mup genes have recently duplicated in rodents, and in house mice they form a cluster of 21 coding genes (and a similar number of pseudogenes), which can be divided into two groups, the group-A (ancestral), containing Mup3, Mup4, Mup5, Mup6, Mup20 (or "Darcin"), and Mup21 and the group-B, consisting of 15 other Mups sharing almost 99% sequence identity: Mup1, Mup2, Mup7-Mup19 (Logan et al, 2008;Mudge et al, 2008), reviewed in Janotová and Stopka (2009), Stopková et al (2009), andPhelan et al (2014). The level of urinary MUP production is socially regulated in C57BL/6 laboratory mice and wild living M. m. musculus (Janotova and Stopka, 2011) and M. m. domesticus (Cunningham et al, 2013) mice.…”