Update on the human and mouse lipocalin (LCN) gene family, including evidence the mouse Mup cluster is result of an "evolutionary bloom"

Abstract

Lipocalins (LCNs) are members of a family of evolutionarily conserved genes present in all kingdoms of life. There are 19 LCN-like genes in the human genome, and 45 Lcn-like genes in the mouse genome, which include 22 major urinary protein (Mup) genes. The Mup genes, plus 29 of 30 Mup-ps pseudogenes, are all located together on chromosome (Chr) 4; evidence points to an "evolutionary bloom" that resulted in this Mup cluster in mouse, syntenic to the human Chr 9q32 locus at which a single MUPP pseudogene is located. LCNs play important roles in physiological processes by binding and transporting small hydrophobic molecules -such as steroid hormones, odorants, retinoids, and lipids-in plasma and other body fluids. LCNs are extensively used in clinical practice as biochemical markers. LCN-like proteins (18-40 kDa) have the characteristic eight β-strands creating a barrel structure that houses the binding-site; LCNs are synthesized in the liver as well as various secretory tissues. In rodents, MUPs are involved in communication of information in urine-derived scent marks, serving as signatures of individual identity, or as kairomones (to elicit fear behavior). MUPs also participate in regulation of glucose and lipid metabolism via a mechanism not well understood. Although much has been learned about LCNs and MUPs in recent years, more research is necessary to allow better understanding of their physiological functions, as well as their involvement in clinical disorders.

Fig. 1

Dendrogram of lipocalins (LCNs) in the human genome. Although the names listed are the official human gene symbols [https://www.genenames.org/], this dendrogram is based on the alignment of proteins (listed in Table 1), using multiple sequence alignment by CLUSTALW (http://www.genome.jp/tools/clustalw/)

Fig. 2

Dendrogram of mouse Lcn and Mup proteins. Although the names listed are the official mouse gene symbols [http://www.informatics.jax.org/], this dendrogram is based on the alignment of proteins (listed in Tables 1 and 2), using multiple sequence alignment by CLUSTALW (http://www.genome.jp/tools/clustalw/)

Fig. 3

Structure of prototypical mouse urinary protein. The crystal structure consists of eight β-strands, forming a calyx-shaped barrel (red); this encloses an internal ligand-binding site. There are also an α-helix (green) and four 3₁₀-helices (blue); the hydrophobic pocket is located inside the barrel. AB, BC, CD, DE, EF, FG, GH, HI, AND βI denote the amino-acid segments between the β-strands (This diagram taken from Ref. [95])

Fig. 4

Chromosomal location of mouse Mup genes and pseudogenes. a The Mup cluster region, located at 60,498,012 Mb to 60,501,960 Mb (red vertical rectangle). Taken from the Ensembl genome browser. b The Chr 4 region (in greater detail)—showing ten of the 22 Mup genes (Gm21320 is Mup22) in the Mup cluster and 12 of the 29 Mup-ps pseudogenes

Fig. 5

Dendrogram of human LCNs and mouse MUPs, combined. Although the names listed are the official human gene symbols and mouse Mup gene symbols, this dendrogram was based on the alignment of proteins (listed in Tables 1 and 3) using multiple sequence alignment by CLUSTALW (http://www.genome.jp/tools/clustalw/). Note that the human LCN9 gene is evolutionarily closest to the mouse Mup cluster in this dendrogram