TCDB is operated by the Saier Lab Bioinformatics Group
« See all members of the family


2.A.29.3.2
Mitochondrial brown fat uncoupling protein 1 (UCP1 or UCP-1)  is also called thermogenin and obesity protein (SLC25A7). It mediates adaptive thermogenesis (Azzu and Brand, 2009).  It transports protons and chloride ions and is activated by fatty acids while being inhibited by purine nucleotides (Hoang et al. 2012).  It functions as a long-chain fatty acid (LCFA) anion/H+ symporter, but the LCFA anion can not dissociate due to hydrophobic interactions, so it is, in effect, an H+ carrier (Fedorenko et al. 2012).  Thermogenic Brown adipose tissue cells with increased UCP1 activity also have increased ATP sythase activity to allow maintenance of normal ATP levels (Guillen et al. 2013). Zhao et al. 2017 showed that fatty acids (FA) can directly bind UCP1 at a helix-helix interface site composed of residues from TMSs H1 and H6. The FA acyl chain appears to fit into the groove between H1 and H6 while the FA carboxylate group interacts with the basic residues near the matrix side of UCP1 (Zhao et al. 2017). UCP1 mediates liver injury in mice and humans by modulating mitochondrial ATP production and cell apoptosis via the ERK signaling pathway (Liu et al. 2017). Activation is achieved by retinoids of UCP1 (Tomás et al. 2004). Expression of its structural gene is influenced by emodin (Cheng et al. 2021). Repeated oral administration of flavan-3-ols induces browning in mice adipose tissues through sympathetic nerve activation, and this involves increased synthesis of UCP-1, CD137 (TC# 9.B.87.4.2) and TMEM26 (TC# 9.B.422.1.1) (Ishii et al. 2021). UCP1 has been described in detail as a sophisticated energy valve involving loose and tight conformations and H+ transport (Klingenberg 2017). H+ transport is electrophoretic and depends on fatty acids. By alternating opening of the gates, the fatty acid takes H+ from cytosol and release it to the matrix (Klingenberg 2017). ucp1, and ucp3, biomarkers for cardiac damage, were significantly upregulated by Tl+ in Danio rerio. (Chang et al. 2023). The cryo-EM structure of the GTP-inhibited state of UCP1, like its nonconducting state, has been solved (Jones et al. 2023). The purine nucleotide cross-links the transmembrane helices of UCP1 with an extensive interaction network, providing a structural basis for understanding the specificity and pH dependency of this regulatory mechanism. The analyses indicate that inhibitor binding prevents the conformational changes that UCP1 uses to facilitate proton leak (Jones et al. 2023). As noted above, UCP1 conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of protons into heat.  UCP1 is activated by endogenous fatty acids and synthetic small molecules, such as 2,4-dinitrophenol (DNP), and is inhibited by purine nucleotides, such as ATP. Kang and Chen 2023 presented the structures of human UCP1 in the nucleotide-free state, the DNP-bound state and the ATP- bound state. The structures show that the central cavity of UCP1 is open to the cytosolic side. DNP binds inside the cavity, making contact with TMS2 and TM6. ATP binds in the same cavity and induces conformational changes in TMS2, together with the inward bending of TMSs 1, 4, 5 and 6 of UCP1, resulting in a more compact structure of UCP1. The binding site of ATP overlaps that of DNP, suggesting that ATP competitively blocks the functional engagement of DNP, resulting in the inhibition of the proton-conducting activity of UCP1 (Kang and Chen 2023).  Mitochondrial H+ leak and thermogenesis involves the function and regulation of uncoupling protein 1 and the ADP/ATP carrier, the two proteins that mediate mitochondrial H+ leak. (Bertholet and Kirichok 2022)

Accession Number:P25874
Protein Name:Mitochondrial brown fat uncoupling protein 1 (UCP1) (thermogenin) aka obesity protein (SLC25A7)
Length:307
Molecular Weight:33005.00
Species:Homo sapiens (Human) [9606]
Location1 / Topology2 / Orientation3: Mitochondrion inner membrane1 / Multi-pass membrane protein2
Substrate chloride, hydron, fatty acid

Cross database links:

RefSeq: NP_068605.1   
Entrez Gene ID: 7350   
Pfam: PF00153   
OMIM: 113730  gene
KEGG: hsa:7350    hsa:7350   

Gene Ontology

GO:0016021 C:integral to membrane
GO:0005743 C:mitochondrial inner membrane
GO:0050873 P:brown fat cell differentiation
GO:0006839 P:mitochondrial transport
GO:0015992 P:proton transport
GO:0055085 P:transmembrane transport
GO:0017077 F:oxidative phosphorylation uncoupler activity
GO:0032870 P:cellular response to hormone stimulus
GO:0006357 P:regulation of transcription from RNA polymerase II promoter
GO:0022904 P:respiratory electron transport chain
GO:0048545 P:response to steroid hormone stimulus
GO:0044281 P:small molecule metabolic process

References (12)

[1] “Human uncoupling protein gene: structure, comparison with rat gene, and assignment to the long arm of chromosome 4.”  Cassard A.M.et.al.   2380264
[2] “Generation and annotation of the DNA sequences of human chromosomes 2 and 4.”  Hillier L.W.et.al.   15815621
[3] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[4] “Detection of brown adipose tissue uncoupling protein mRNA in adult patients by a human genomic probe.”  Bouillaud F.et.al.   3165741
[5] “A polymorphism in the 5' untranslated region and a Met229-->Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type II diabetes mellitus.”  Mori H.et.al.   11317671
[6] “Uncoupling protein 1 and 3 polymorphisms are associated with waist-to-hip ratio.”  Herrmann S.M.et.al.   12756473
[7] “Human uncoupling protein gene: structure, comparison with rat gene, and assignment to the long arm of chromosome 4.”  Cassard A.M.et.al.   2380264
[8] “Generation and annotation of the DNA sequences of human chromosomes 2 and 4.”  Hillier L.W.et.al.   15815621
[9] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[10] “Detection of brown adipose tissue uncoupling protein mRNA in adult patients by a human genomic probe.”  Bouillaud F.et.al.   3165741
[11] “A polymorphism in the 5' untranslated region and a Met229-->Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type II diabetes mellitus.”  Mori H.et.al.   11317671
[12] “Uncoupling protein 1 and 3 polymorphisms are associated with waist-to-hip ratio.”  Herrmann S.M.et.al.   12756473

External Searches:

Analyze:

Predict TMSs (Predict number of transmembrane segments)
Window Size: Angle:  
FASTA formatted sequence
1:	MGGLTASDVH PTLGVQLFSA GIAACLADVI TFPLDTAKVR LQVQGECPTS SVIRYKGVLG 
61:	TITAVVKTEG RMKLYSGLPA GLQRQISSAS LRIGLYDTVQ EFLTAGKETA PSLGSKILAG 
121:	LTTGGVAVFI GQPTEVVKVR LQAQSHLHGI KPRYTGTYNA YRIIATTEGL TGLWKGTTPN 
181:	LMRSVIINCT ELVTYDLMKE AFVKNNILAD DVPCHLVSAL IAGFCATAMS SPVDVVKTRF 
241:	INSPPGQYKS VPNCAMKVFT NEGPTAFFKG LVPSFLRLGS WNVIMFVCFE QLKRELSKSR 
301:	QTMDCAT