30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function

  1. Yoshinao Katsu2
  1. 1Division of Nephrology-Hypertension, Department of Medicine, University of California, San Diego, CA, USA
  2. 2Graduate School of Life Science, Hokkaido University, Sapporo, Japan
  1. Correspondence should be addressed to M E Baker or Y Katsu; Email: mbaker{at}ucsd.edu or ykatsu{at}sci.hokudai.ac.jp
  1. Figure 1

    MR, GR, PR, AR and ER in vertebrates. The ER, CR and PR are found in lampreys and hagfish, which are jawless fishes (cyclostomes) that evolved at the base of the vertebrate line. A separate MR and GR are found in cartilaginous fish (Chondrichthyes), which are divided into the subclass Elasmobranchii containing sharks, skates and rays and the subclass Holocephali (chimeras) containing elephant sharks and which together are basal jawed vertebrates. These basal jawed vertebrates, which contain cartilage instead of bone, are forerunners of bony fishes, which are divided into the subclass Actinopterygii (ray-finned fish) containing, for example, sturgeon, zebrafish and salmon, and the subclass Sarcopterygii (lobe-finned fish ) containing coelacanths and lungfish, which are forerunners of tetrapods (land vertebrates). The AR first appears in cartilaginous fishes.

  2. Figure 2

    Structures of mineralocorticoids and glucocorticoids. Aldosterone [Aldo] and 11-deoxycorticosterone [DOC] are the main physiological mineralocorticoids in vertebrates. Cortisol [F] and corticosterone [B] are the main physiological glucocorticoids in vertebrates. 11-deoxycortisol [S] has activity as mineralocorticoid and glucocorticoid in lamprey CR (Baker 2011). Progesterone [Prog] is an antagonist for human MR (Rupprecht et al. 1993b, Geller 2000) and an agonist for fish MRs (Sturm et al. 2005, Pippal et al. 2011, Sugimoto et al. 2016).

  3. Figure 3

    Pathway for the synthesis of aldosterone from progesterone and cortisol from 17α-OH-Progesterone. Progesterone is hydroxylated at C21 to form 11-deoxycorticosterone, which is hydroxylated at C11 to form corticosterone. Hydroxylated corticosterone at C18 followed by oxidation of the C18 hydroxyl forms aldosterone. In a second pathway, progesterone is hydroxylated at C17 and then hydroxylated at C21 to form 11-deoxycortisol, which is hydroxylated at C11 to form cortisol (Baker 2011, Rossier et al. 2015).

  4. Figure 4

    Comparison of domains on MR, GR, PR, AR and CR. The A/B domain to E domains are schematically represented with the numbers of amino acid residues and the percentage of amino acid identity between the domains compared to human MR. For example, the entire human MR sequence is 82% identical to that of chicken MR, while domain E (LBD) on human MR is 93% identical to that of chicken MR. Accessions are in Supplement Table 1 (see section on supplementary data given at the end of this article).

  5. Figure 5

    Alignment of the steroid-binding domain on vertebrate MRs, CRs, GRs, PRs and AR. The steroid-binding domains were collected with BLAST searches of GenBank. Clustal W2 was used to construct the multiple alignment (Larkin et al. 2007). The crystal structure of human MR (PDB: 2A3I) (Li et al. 2005) was used to locate α-helices. Amino acids that contact Aldo are shown above human MR. The highly conserved Glu-962 is part of AF2, which contacts coactivator proteins. The functions of Ser-949 and His-950 remain to be elucidated.

  6. Figure 6

    Phylogenetic analysis of vertebrate MRs, GRs, CRs, PRs and ARs. Steroid-binding domains were collected with BLAST searches of GenBank. Then Clustal W2 (Larkin et al. 2007) was used to construct the multiple alignment. The phylogenetic tree was constructed using Maximum Likelihood based on the JTT matrix-based model (Jones et al. 1992). Statistical confidence for each branch in the tree was evaluated with 1,000 bootstrap runs (Tamura et al. 2011). The tree indicates that the CR/PR ancestor in an ancestral cyclostome duplicated to form genes that evolved into the CR and PR in modern lampreys and hagfishes. Subsequently, the ancestral CR duplicated, with the surviving CR found in the branch containing descendants in lamprey and hagfish that cluster with lamprey and hagfish PR. The MR and GR are descendants of the other CR that appears to be lost in lamprey and hagfish (Baker et al. 2015, Rossier et al. 2015). In Gnathostomes, a gene duplication produced the AR and PR.

  7. Figure 7

    Contacts between the MR and Aldo and two water molecules. Contacts between Aldo with human MR (PDB: 2AA2) (Bledsoe et al. 2005) are shown. Two water molecules mediate contacts between Ser-810 and the A ring of Aldo.

  8. Figure 8

    Comparison of Ser-843/Leu-848 on human MR with Pro-637/Gln-642 on human GR. Human GR complexed with dexamethasone (PDB: 1M2Z) (Bledsoe et al. 2002) and human MR complexed with dexamethasone (PDB: 4UDA) (Edman et al. 2015) were superimposed. In human MR, Cδ1 on Leu-848 is 6.2 Ǻ and 3.8 Ǻ, respectively, from 17α-OH and 16α-CH3 on DEX. In human GR, Oε1 is 3.0 Ǻ and 3.6 Ǻ, respectively, from 17α-OH and 16α-CH3 on DEX. Ser-843 and Pro-637 are displaced by over 5 Ǻ.

  9. Figure 9

    Superposition of helix 12 and the preceding loop in human MR and human GR. Human GR has a deletion corresponding to Ser-949 in human MR, which is in the loop connecting helix 11 and helix 12 in human MR. In human GR, this deletion displaces Oδ2 on Glu-755 in helix 12 on human GR from Oδ2 on Glu-962 in human MR by 3.5 Ǻ. In the loop preceding helix 12, Nζ on Lys-743 on human GR is 3 Ǻ from Nε2 on His-950 on human MR. Glu-755 and Glu-962 in the AF2 domain are highly conserved and are part of charge clamp 1 between coactivators and the GR and MR (Li et al. 2005, Kattoula & Baker 2014).

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