Reviewed, UniProtKB/Swiss-Prot P08235 (MCR_HUMAN)

Names and origin

Protein names

Mineralocorticoid receptor
Also known as:
     MR
     Nuclear receptor subfamily 3 group C member 2

Gene names

Name:	NR3C2
Synonyms:	MCR, MLR

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein existence

Evidence at protein level.

General annotation (Comments)

Function	Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels.
Subunit structure	Heteromultimeric cytoplasmic complex with HSP90, HSP70, and FKBP4, in the absence of ligand. After ligand binding, it translocates to the nucleus and binds to DNA as a homodimer and as a heterodimer with NR3C1. May interact with HSD11B2 in the absence of ligand. Binds the coactivators NCOA1, NCOA2, TIF1 and NRIP1.
Subcellular location	Cytoplasm. Nucleus. Endoplasmic reticulum membrane; Peripheral membrane protein. Note=Cytoplasmic and nuclear in the absence of ligand; nuclear after ligand-binding. When bound to HSD11B2, it is found associated with the endoplasmic reticulum membrane.
Tissue specificity	Ubiquitous. Highly expressed in distal tubules, convoluted tubules and cortical collecting duct in kidney, and in sweat glands. Detected at lower levels in cardiomyocytes, in epidermis and in colon enterocytes.
Domain	Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal steroid-binding domain.
Post-translational modification	Phosphorylated.
Involvement in disease	Defects in NR3C2 are a cause of autosomal dominant pseudohypoaldosteronism type I (PHA1) [MIM:177735]. PHA1 is characterized by urinary salt wasting, resulting from target organ unresponsiveness to mineralocorticoids. There are 2 forms of PHA1: the autosomal dominant form that is mild, and the recessive form which is more severe and due to defects in any of the epithelial sodium channel subunits. In autosomal dominant PHA1 the target organ defect is confined to kidney. Clinical expression can vary from asymptomatic to moderate. It may be severe at birth, but symptoms remit with age. Familial and sporadic cases have been reported. Defects in NR3C2 are a cause of early onset hypertension with severe exacerbation in pregnancy [MIM:605115]. Inheritance is autosomal dominant. The disease is characterized by the onset of severe hypertension before the age of 20, and by suppression of aldosterone secretion.
Sequence similarities	Belongs to the nuclear hormone receptor family. NR3 subfamily. Contains 1 nuclear receptor DNA-binding domain.

Ontologies

Keywords
Biological process	Transcription Transcription regulation
Cellular component	Cytoplasm Endoplasmic reticulum Membrane Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Zinc-finger
Ligand	DNA-binding Lipid-binding Metal-binding Steroid-binding Zinc
Molecular function	Receptor
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	signal transduction Ref.1 Traceable author statement. Source: ProtInc
Molecular function	protein binding Ref.2 Inferred from physical interaction. Source: UniProtKB steroid hormone receptor activity Ref.3 Traceable author statement. Source: ProtInc transcription factor activity Ref.1 Traceable author statement. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. Notes: Additional isoforms seem to exist. [Align] [Select]

Isoform 1 (identifier: P08235-1)
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P08235-2)
The sequence of this isoform differs from the canonical sequence as follows:
     672-706 ARKSKKLGKLKGIHEEQPQQQQPPPPPPPPQSPEE → ERRCISLPCMNYARGCTKSAFSSFDCSSPLKNTPS
     707-984: Missing.
Notes: Lacks steroid-binding activity and acts as ligand-independent transactivator.

Isoform 3 (identifier: P08235-3)
The sequence of this isoform differs from the canonical sequence as follows:
     633-633 G → GKCSW

Isoform 4 (identifier: P08235-4)
Also known as Delta;
The sequence of this isoform differs from the canonical sequence as follows:
     672-788: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 984

984

Mineralocorticoid receptor

Regions

DNA binding

603 – 668

66

Nuclear receptor

Zinc finger

603 – 623

21

NR C4-type

Zinc finger

639 – 663

25

NR C4-type

Region

1 – 602

602

Modulating

Region

669 – 732

64

Hinge

Region

733 – 984

252

Steroid-binding

Region

782 – 785

4

Important for coactivator binding

Sites

Binding site

770

1

Steroid

Binding site

776

1

Steroid

Binding site

817

1

Steroid

Binding site

945

1

Steroid

Natural variations

Alternative sequence

633

1

G → GKCSW in isoform 3.

Alternative sequence

672 – 788

117

Missing in isoform 4.

Alternative sequence

672 – 706

35

ARKSK…QSPEE → ERRCISLPCMNYARGCTKSA FSSFDCSSPLKNTPS in isoform 2.

Alternative sequence

707 – 984

278

Missing in isoform 2.

Natural variant

7

1

H → Q in a colorectal cancer sample; somatic mutation.

Natural variant

180

1

I → V High frequency in healthy individuals; found in a patient with sporadic pseudohypoaldosteronism type I; increases transcription transactivation at low aldosterone concentrations. dbSNP rs5522.

Natural variant

241

1

A → V High frequency in healthy individuals; found in a patient with sporadic pseudohypoaldosteronism type I; reduces transcription transactivation upon aldosterone binding.

Natural variant

444

1

N → T: dbSNP rs5523.

Natural variant

537

1

R → Q: dbSNP rs5526.

Natural variant

554

1

N → S: dbSNP rs5527.

Natural variant

633

1

G → R in PHA1; reduces transcription transactivation upon aldosterone binding.

Natural variant

645

1

C → S in PHA1.

Natural variant

659

1

R → S in PHA1.

Natural variant

759

1

P → S in PHA1.

Natural variant

769

1

L → P in PHA1.

Natural variant

770

1

N → K in PHA1.

Natural variant

776

1

Q → R in PHA1; reduces aldosterone binding.

Natural variant

805

1

S → P in PHA1.

Natural variant

810

1

S → L in early onset hypertension; alters receptor specificity and leads to constitutive activation.

Natural variant

815

1

S → R in PHA1.

Natural variant

818

1

S → L in PHA1; abolishes translocation to the nucleus and transcription transactivation upon aldosterone binding.

Natural variant

826

1

F → Y: dbSNP rs13306592.

Natural variant

924

1

L → P in PHA1; abolishes transcription transactivation upon aldosterone binding.

Natural variant

972

1

E → G in PHA1; reduces affinity for aldosterone and transcription transactivation.

Natural variant

979

1

L → P in PHA1; loss of aldosterone binding and transcription transactivation.

Experimental info

Mutagenesis

767

1

S → N: Loss of transcription transactivation

Mutagenesis

767

1

S → Q: Strong decrease of transcription transactivation

Mutagenesis

770

1

N → A, D, H, Q, S or T: Abolishes aldosterone binding and transcription transactivation

Mutagenesis

776

1

Q → A: Reduces aldosterone binding and transcription transactivation

Mutagenesis

782

1

K → E: Decreased coactivator binding

Mutagenesis

785

1

K → E: Loss of coactivator binding

Mutagenesis

796

1

E → R: Decreased coactivator binding

Mutagenesis

808

1

C → S: Increases aldosterone-binding

Mutagenesis

810

1

S → M: Alters receptor specificity

Mutagenesis

817

1

R → A: Reduces aldosterone binding and transcription transactivation

Mutagenesis

849

1

C → S: Strongly decreases affinity for aldosterone and transcription transactivation

Mutagenesis

942

1

C → S: Abolishes steroid binding and transcription transactivation

Mutagenesis

945

1

T → A: Decreases aldosterone-binding and cortisol-binding

Mutagenesis

952

1

L → A: Reduces transcription transactivation

Mutagenesis

953

1

K → A: Slightly reduces aldosterone binding and abolishes transcription transactivation

Mutagenesis

954

1

V → A: Reduces aldosterone binding and abolishes transcription transactivation

Mutagenesis

956

1

F → A: Abolishes aldosterone binding and transcription transactivation

Mutagenesis

957

1

P → A: Slightly reduces aldosterone binding and transcription transactivation

Secondary structure

1

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984

Helix Strand Turn

Details...

Helix

738 – 745

8

Helix

762 – 784

23

Helix

790 – 792

3

Helix

795 – 822

28

Beta strand

825 – 830

6

Beta strand

833 – 835

3

Turn

837 – 840

4

Helix

841 – 843

3

Turn

846 – 848

3

Helix

849 – 862

14

Helix

866 – 877

12

Beta strand

879 – 882

4

Helix

889 – 907

19

Helix

918 – 947

30

Helix

949 – 952

4

Helix

961 – 971

11

Beta strand

976 – 978

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified August 1, 1988. Version 1. Checksum: 8300CD1A18C1858A	FASTA	984	107,067
	10 20 30 40 50 60 METKGYHSLP EGLDMERRWG QVSQAVERSS LGPTERTDEN NYMEIVNVSC VSGAIPNNST 70 80 90 100 110 120 QGSSKEKQEL LPCLQQDNNR PGILTSDIKT ELESKELSAT VAESMGLYMD SVRDADYSYE 130 140 150 160 170 180 QQNQQGSMSP AKIYQNVEQL VKFYKGNGHR PSTLSCVNTP LRSFMSDSGS SVNGGVMRAI 190 200 210 220 230 240 VKSPIMCHEK SPSVCSPLNM TSSVCSPAGI NSVSSTTASF GSFPVHSPIT QGTPLTCSPN 250 260 270 280 290 300 AENRGSRSHS PAHASNVGSP LSSPLSSMKS SISSPPSHCS VKSPVSSPNN VTLRSSVSSP 310 320 330 340 350 360 ANINNSRCSV SSPSNTNNRS TLSSPAASTV GSICSPVNNA FSYTASGTSA GSSTLRDVVP 370 380 390 400 410 420 SPDTQEKGAQ EVPFPKTEEV ESAISNGVTG QLNIVQYIKP EPDGAFSSSC LGGNSKINSD 430 440 450 460 470 480 SSFSVPIKQE STKHSCSGTS FKGNPTVNPF PFMDGSYFSF MDDKDYYSLS GILGPPVPGF 490 500 510 520 530 540 DGNCEGSGFP VGIKQEPDDG SYYPEASIPS SAIVGVNSGG QSFHYRIGAQ GTISLSRSAR 550 560 570 580 590 600 DQSFQHLSSF PPVNTLVESW KSHGDLSSRR SDGYPVLEYI PENVSSSTLR SVSTGSSRPS 610 620 630 640 650 660 KICLVCGDEA SGCHYGVVTC GSCKVFFKRA VEGQHNYLCA GRNDCIIDKI RRKNCPACRL 670 680 690 700 710 720 QKCLQAGMNL GARKSKKLGK LKGIHEEQPQ QQQPPPPPPP PQSPEEGTTY IAPAKEPSVN 730 740 750 760 770 780 TALVPQLSTI SRALTPSPVM VLENIEPEIV YAGYDSSKPD TAENLLSTLN RLAGKQMIQV 790 800 810 820 830 840 VKWAKVLPGF KNLPLEDQIT LIQYSWMCLS SFALSWRSYK HTNSQFLYFA PDLVFNEEKM 850 860 870 880 890 900 HQSAMYELCQ GMHQISLQFV RLQLTFEEYT IMKVLLLLST IPKDGLKSQA AFEEMRTNYI 910 920 930 940 950 960 KELRKMVTKC PNNSGQSWQR FYQLTKLLDS MHDLVSDLLE FCFYTFRESH ALKVEFPAML 970 980 VEIISDQLPK VESGNAKPLY FHRK
	Isoform 2 [UniParc]. Checksum: EEFC58BB02FA0812		706	75,052
	10 20 30 40 50 60 METKGYHSLP EGLDMERRWG QVSQAVERSS LGPTERTDEN NYMEIVNVSC VSGAIPNNST 70 80 90 100 110 120 QGSSKEKQEL LPCLQQDNNR PGILTSDIKT ELESKELSAT VAESMGLYMD SVRDADYSYE 130 140 150 160 170 180 QQNQQGSMSP AKIYQNVEQL VKFYKGNGHR PSTLSCVNTP LRSFMSDSGS SVNGGVMRAI 190 200 210 220 230 240 VKSPIMCHEK SPSVCSPLNM TSSVCSPAGI NSVSSTTASF GSFPVHSPIT QGTPLTCSPN 250 260 270 280 290 300 AENRGSRSHS PAHASNVGSP LSSPLSSMKS SISSPPSHCS VKSPVSSPNN VTLRSSVSSP 310 320 330 340 350 360 ANINNSRCSV SSPSNTNNRS TLSSPAASTV GSICSPVNNA FSYTASGTSA GSSTLRDVVP 370 380 390 400 410 420 SPDTQEKGAQ EVPFPKTEEV ESAISNGVTG QLNIVQYIKP EPDGAFSSSC LGGNSKINSD 430 440 450 460 470 480 SSFSVPIKQE STKHSCSGTS FKGNPTVNPF PFMDGSYFSF MDDKDYYSLS GILGPPVPGF 490 500 510 520 530 540 DGNCEGSGFP VGIKQEPDDG SYYPEASIPS SAIVGVNSGG QSFHYRIGAQ GTISLSRSAR 550 560 570 580 590 600 DQSFQHLSSF PPVNTLVESW KSHGDLSSRR SDGYPVLEYI PENVSSSTLR SVSTGSSRPS 610 620 630 640 650 660 KICLVCGDEA SGCHYGVVTC GSCKVFFKRA VEGQHNYLCA GRNDCIIDKI RRKNCPACRL 670 680 690 700 QKCLQAGMNL GERRCISLPC MNYARGCTKS AFSSFDCSSP LKNTPS
	Isoform 3 [UniParc]. Checksum: D6257319E5482C86		988	107,572
	10 20 30 40 50 60 METKGYHSLP EGLDMERRWG QVSQAVERSS LGPTERTDEN NYMEIVNVSC VSGAIPNNST 70 80 90 100 110 120 QGSSKEKQEL LPCLQQDNNR PGILTSDIKT ELESKELSAT VAESMGLYMD SVRDADYSYE 130 140 150 160 170 180 QQNQQGSMSP AKIYQNVEQL VKFYKGNGHR PSTLSCVNTP LRSFMSDSGS SVNGGVMRAI 190 200 210 220 230 240 VKSPIMCHEK SPSVCSPLNM TSSVCSPAGI NSVSSTTASF GSFPVHSPIT QGTPLTCSPN 250 260 270 280 290 300 AENRGSRSHS PAHASNVGSP LSSPLSSMKS SISSPPSHCS VKSPVSSPNN VTLRSSVSSP 310 320 330 340 350 360 ANINNSRCSV SSPSNTNNRS TLSSPAASTV GSICSPVNNA FSYTASGTSA GSSTLRDVVP 370 380 390 400 410 420 SPDTQEKGAQ EVPFPKTEEV ESAISNGVTG QLNIVQYIKP EPDGAFSSSC LGGNSKINSD 430 440 450 460 470 480 SSFSVPIKQE STKHSCSGTS FKGNPTVNPF PFMDGSYFSF MDDKDYYSLS GILGPPVPGF 490 500 510 520 530 540 DGNCEGSGFP VGIKQEPDDG SYYPEASIPS SAIVGVNSGG QSFHYRIGAQ GTISLSRSAR 550 560 570 580 590 600 DQSFQHLSSF PPVNTLVESW KSHGDLSSRR SDGYPVLEYI PENVSSSTLR SVSTGSSRPS 610 620 630 640 650 660 KICLVCGDEA SGCHYGVVTC GSCKVFFKRA VEGKCSWQHN YLCAGRNDCI IDKIRRKNCP 670 680 690 700 710 720 ACRLQKCLQA GMNLGARKSK KLGKLKGIHE EQPQQQQPPP PPPPPQSPEE GTTYIAPAKE 730 740 750 760 770 780 PSVNTALVPQ LSTISRALTP SPVMVLENIE PEIVYAGYDS SKPDTAENLL STLNRLAGKQ 790 800 810 820 830 840 MIQVVKWAKV LPGFKNLPLE DQITLIQYSW MCLSSFALSW RSYKHTNSQF LYFAPDLVFN 850 860 870 880 890 900 EEKMHQSAMY ELCQGMHQIS LQFVRLQLTF EEYTIMKVLL LLSTIPKDGL KSQAAFEEMR 910 920 930 940 950 960 TNYIKELRKM VTKCPNNSGQ SWQRFYQLTK LLDSMHDLVS DLLEFCFYTF RESHALKVEF 970 980 PAMLVEIISD QLPKVESGNA KPLYFHRK
	Isoform 4 (Delta) [UniParc]. Checksum: BEC8DD3A6A855903		867	94,359
	10 20 30 40 50 60 METKGYHSLP EGLDMERRWG QVSQAVERSS LGPTERTDEN NYMEIVNVSC VSGAIPNNST 70 80 90 100 110 120 QGSSKEKQEL LPCLQQDNNR PGILTSDIKT ELESKELSAT VAESMGLYMD SVRDADYSYE 130 140 150 160 170 180 QQNQQGSMSP AKIYQNVEQL VKFYKGNGHR PSTLSCVNTP LRSFMSDSGS SVNGGVMRAI 190 200 210 220 230 240 VKSPIMCHEK SPSVCSPLNM TSSVCSPAGI NSVSSTTASF GSFPVHSPIT QGTPLTCSPN 250 260 270 280 290 300 AENRGSRSHS PAHASNVGSP LSSPLSSMKS SISSPPSHCS VKSPVSSPNN VTLRSSVSSP 310 320 330 340 350 360 ANINNSRCSV SSPSNTNNRS TLSSPAASTV GSICSPVNNA FSYTASGTSA GSSTLRDVVP 370 380 390 400 410 420 SPDTQEKGAQ EVPFPKTEEV ESAISNGVTG QLNIVQYIKP EPDGAFSSSC LGGNSKINSD 430 440 450 460 470 480 SSFSVPIKQE STKHSCSGTS FKGNPTVNPF PFMDGSYFSF MDDKDYYSLS GILGPPVPGF 490 500 510 520 530 540 DGNCEGSGFP VGIKQEPDDG SYYPEASIPS SAIVGVNSGG QSFHYRIGAQ GTISLSRSAR 550 560 570 580 590 600 DQSFQHLSSF PPVNTLVESW KSHGDLSSRR SDGYPVLEYI PENVSSSTLR SVSTGSSRPS 610 620 630 640 650 660 KICLVCGDEA SGCHYGVVTC GSCKVFFKRA VEGQHNYLCA GRNDCIIDKI RRKNCPACRL 670 680 690 700 710 720 QKCLQAGMNL GGFKNLPLED QITLIQYSWM CLSSFALSWR SYKHTNSQFL YFAPDLVFNE 730 740 750 760 770 780 EKMHQSAMYE LCQGMHQISL QFVRLQLTFE EYTIMKVLLL LSTIPKDGLK SQAAFEEMRT 790 800 810 820 830 840 NYIKELRKMV TKCPNNSGQS WQRFYQLTKL LDSMHDLVSD LLEFCFYTFR ESHALKVEFP 850 860 AMLVEIISDQ LPKVESGNAK PLYFHRK

References

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