Major urinary proteins

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alpha helices (red) at both the amino- and carboxyl termini. The structure is resolved from Protein Data Bank entry 1i04. Find all instances
of this protein in the PDB

Major urinary proteins (Mups), also known as α2u-globulins, are a subfamily of proteins found in abundance in the urine and other secretions of many animals. Mups provide a small range of identifying information about the donor animal, when detected by the vomeronasal organ of the receiving animal. They belong to a larger family of proteins known as lipocalins. Mups are encoded by a cluster of genes, located adjacent to each other on a single stretch of DNA, that varies greatly in number between species: from at least 21 functional genes in mice to none in humans. Mup proteins form a characteristic glove shape, encompassing a ligand-binding pocket that accommodates specific small organic chemicals.

Urinary proteins were first reported in rodents in 1932, during studies by

endogenous function within an animal is unknown but may involve regulating energy expenditure. However, as secreted proteins they play multiple roles in chemical communication between animals, functioning as pheromone transporters and stabilizers in rodents and pigs. Mups can also act as protein pheromones themselves. They have been demonstrated to promote aggression in male mice, and one specific Mup protein found in male mouse urine is sexually attractive to female mice. Mups can also function as signals between different species
: mice display an instinctive fear response on the detection of Mups derived from predators such as cats and rats.

Discovery

Phylogeny of Mup coding sequences in mammals.[1] The repeatability of the reconstruction was tested by bootstrapping
. Interior branches with bootstrap support > 50% are shown.

Humans in good health excrete urine that is largely free of protein. Therefore, since 1827 physicians and scientists have been interested in proteinuria, the excess of protein in human urine, as an indicator of kidney disease.[notes 1][2] To better understand the etiology of proteinuria, some scientists attempted to study the phenomenon in laboratory animals.[3] Between 1932 and 1933 a number of scientists, including Thomas Addis, independently reported the surprising finding that some healthy rodents have protein in their urine.[4][5][6] However, it was not until the 1960s that the major urinary proteins of mice and rats were first described in detail.[7][8] It was found that the proteins are primarily made in the liver of males and secreted through the kidneys into the urine in large quantities (milligrams per day).[7][8][9]

Since they were named, the proteins have been found to be differentially expressed in other

mammary glands.[10][11][12] In some species, such as cats and pigs, Mups appear not to be expressed in urine at all and are mainly found in saliva.[13][14] Sometimes the term urinary Mups (uMups) is used to distinguish those Mups expressed in urine from those in other tissues.[15]

Mup genes

Between 1979 and 1981, it was estimated that Mups are encoded by a

DNA sequence of whole genomes.[1][19]

Rodents

A dot plot showing different patterns of self-similarity within the first five genes of the mouse Mup cluster
A dot plot showing self-similarity within the mouse Mup cluster.[20] The main diagonal represents the sequence's alignment with itself; lines off the main diagonal represent similar or repetitive patterns within the cluster. The pattern differs between the older, peripheral Class A and the newer, central Class B Mups.

The mouse

whole genome sequence with gaps remaining, and further genes may remain undiscovered.[1][20]

Rat urine also contains homologous urinary proteins; although they were originally given a different name, α2u-globulins,[8][9] they have since become known as rat Mups.[21][22] Rats have 9 distinct Mup genes and a further 13 pseudogenes clustered together across 1.1 megabases of DNA on chromosome 5. Like in mice, the cluster formed by multiple duplications. However, this occurred independently of the duplications in mice, meaning that both rodent species expanded their Mup gene families separately, but in parallel.[1][23]

Nonrodents

Most other mammals studied, including the pig, cow, cat, dog, bushbaby, macaque, chimpanzee and orangutan, have a single Mup gene. Some, however, have an expanded number: horses have three Mup genes, and

placental mammals found not to have any active Mup genes; instead, they have a single Mup pseudogene containing a mutation that causes missplicing, rendering it dysfunctional.[1]

Function

Transport proteins

A ribbon diagram of a mouse major urinary protein with a small chemical ligand in its binding pocket.
Mouse major urinary proteins bind 2-sec-butyl-4,5-dihydrothiazole (SBT), a mouse pheromone.[24] The beta barrel forms a pocket, in which the SBT molecule is tightly bound. The structure is resolved from 1MUP.

Mups are members of a large family of low-

urine scent marks.[31] Given the diversity of Mups in rodents, it was originally thought that different Mups may have differently shaped binding pockets and therefore bind different pheromones. However, detailed studies found that most variable sites are located on the surface of the proteins and appear to have little effect on ligand binding.[32]

Rat Mups bind different small chemicals. The most common ligand is 1-Chloro

nephropathy, that progresses to cancer. Other species do not develop this disorder because their Mups do not bind that particular chemical.[34] Accordingly, when transgenic mice were engineered to express the rat Mup, their kidneys developed the disease.[35]
The Mup found in pigs, named salivary lipocalin (SAL), is expressed in the salivary gland of males where it tightly binds androstenone and androstenol, both pheromones that cause female pigs to assume a mating stance.[1][14]

water molecules. This unusual process has been termed the nonclassical hydrophobic effect.[43]

Pheromones

Different banding patterns of proteins from male and female mouse urine resolved by gel electrophoresis
The Mups in C57BL/6J mouse urine analyzed by native gel electrophoresis

Studies have sought to find the precise function of Mups in pheromone communication. Mup proteins have been shown to promote

sensory receptors, of mice and rats.[19][45] Together, this demonstrated that Mup proteins can act as pheromones themselves, independent of their ligands.[46]

Fitzwilliam Darcy
was the inspiration for the naming of darcin, the Mup that attracts female mice to male urine.

Consistent with a role in male-male aggression, adult male mice secrete significantly more Mups into their urine than females, juveniles or

Fitzwilliam Darcy, the romantic hero from Pride and Prejudice.[52][53] Taken together, the complex patterns of Mups produced has the potential to provide a range of information about the donor animal, such as gender, fertility, social dominance, age, genetic diversity or kinship.[19][54][55] Wild mice (unlike laboratory mice that are genetically identical and which therefore also have identical patterns of Mups in the urine) have individual patterns of Mup expression in their urine that act as a "barcode" to uniquely identify the owner of a scent mark.[54]

In the house mouse, the major MUP gene cluster provides a highly polymorphic scent signal of genetic identity. Wild mice breeding freely in semi-natural enclosures showed inbreeding avoidance. This avoidance resulted from a strong deficit in successful matings between mice sharing both MUP haplotypes (complete match).[56] In another study, using white-footed mice, it was found that when mice derived from wild populations were inbred, there was reduced survival when such mice were reintroduced into a natural habitat.[57] These findings suggest that inbreeding reduces fitness, and that scent signal recognition has evolved in mice as a means of avoiding inbreeding depression.

Kairomones

In addition to serving as social cues between members of the same species, Mups can act as

Rattus norvegicus allergen 1; P02761), the product of the rat Mup13 gene.[59] Mice are fearful of these Mups even when they are made in bacteria, but mutant animals that are unable to detect the Mups showed no fear of rats, demonstrating their importance in initiating fearful behaviour.[58][62] It is not known exactly how Mups from different species initiate disparate behaviours, but mouse Mups and predator Mups have been shown to activate unique patterns of sensory neurons in the nose of recipient mice. This implies the mouse perceives them differently, via distinct neural circuits.[58][59] The pheromone receptors responsible for Mup detection are also unknown, though they are thought be members of the V2R receptor class.[19][59]

Allergens

A ribbon diagram of two identical horse allergen molecules, symmetrically arranged in a crystal structure.
The three-dimensional structure of Equ c 1, shown in the crystallized dimeric form.[63] The structure is resolved from 1EW3.

Along with other members of the lipocalin protein family, major urinary proteins can be potent allergens to humans.

antibodies to Rat n 1.[75]

Mup genes from other mammals also encode allergenic proteins, for example Fel d 4 is primarily produced in the

Equus caballus allergen 1; Q95182) is the protein product of a horse Mup gene that is found in the liver, sublingual and submaxillary salivary glands.[1][76] It is responsible for about 80% of the antibody response in patients who are chronically exposed to horse allergens.[76]

Metabolism

While the detection of Mups excreted by other animals has been well studied, the functional role in the producing animal is less clear. However, in 2009, Mups were shown to be associated with the regulation of energy expenditure in mice. Scientists found that genetically induced obese, diabetic mice produce thirty times less Mup

mitochondrial function in skeletal muscle.[77] Another study found Mups were reduced in diet-induced obese mice. In this case, the presence of Mups in the bloodstream of mice restricted glucose production by directly inhibiting the expression of genes in the liver.[78]

See also

Notes

  1. ^ In that year Richard Bright first related kidney disease, later to become known as Bright's disease, with albuminous urine.

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External links

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