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21  structures 3416  species 0  interactions 4161  sequences 17  architectures

Family: TspO_MBR (PF03073)

Summary: TspO/MBR family

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Translocator protein". More...

Translocator protein Edit Wikipedia article

TSPO
Identifiers
Aliases TSPO, BPBS, BZRP, DBI, IBP, MBR, PBR, PBS, PKBS, PTBR, mDRC, pk18, translocator protein
External IDs OMIM: 109610 MGI: 88222 HomoloGene: 574 GeneCards: TSPO
Gene location (Human)
Chromosome 22 (human)
Chr. Chromosome 22 (human)[1]
Chromosome 22 (human)
Genomic location for TSPO
Genomic location for TSPO
Band 22q13.2 Start 43,151,514 bp[1]
End 43,163,242 bp[1]
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000714
NM_001256530
NM_001256531
NM_007311

NM_009775

RefSeq (protein)

NP_033905

Location (UCSC) Chr 22: 43.15 – 43.16 Mb Chr 15: 83.56 – 83.57 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain.[5] In humans, the translocator protein is encoded by the TSPO gene.[6][7] It belongs to family of tryptophan-rich sensory proteins. Regarding intramitochondrial cholesterol transport, TSPO has been proposed to interact with StAR (steroidogenic acute regulatory protein) to transport cholesterol into mitochondria, though evidence is mixed.[8]

Function

In animals, TSPO (PBR) is a mitochondrial protein usually located in the outer mitochondrial membrane and characterised by its ability to bind a variety of benzodiazepine-like drugs, as well as to dicarboxylic tetrapyrrole intermediates of the haem biosynthetic pathway.

TSPO has many proposed functions depending on the tissue.[9] The most studied of these include roles in the immune response, steroid synthesis and apoptosis.

Cholesterol transport and bile acid biosynthesis

Mitochondrial cholesterol transport is a molecular function closely tied to TSPO in the scientific literature. TSPO binds with high affinity to the lipid cholesterol, and pharmacological ligands of TSPO facilitate cholesterol transport across the mitochondrial intermembrane space to stimulate steroid synthesis and bile acid synthesis in relevant tissues.[10] However, TSPO deletion in genetically engineered mouse models has yielded mixed results regarding the physiological necessity of TSPO's role in steroidogenesis. Deletion of TSPO in steroidogenic Leydig cells did not impair synthesis of the steroid testosterone.[11] Thus, though biochemical and pharmacological experimentation suggest an important role for TSPO in cellular cholesterol transport and steroid biosynthesis,[12] TSPO's necessity in this process remains controversial.

Regulation in the heart

TSPO (Translocator protein) acts to regulate heart rate and contractile force by its interaction with voltage-dependent calcium channels in cardiac myocytes.[13] The interaction between TSPO and calcium channels can alter cardiac action potential durations, thus contractility of the heart. In healthy individuals, TSPO has a cardio-protective role. When TSPO is up-regulated in the presence of infections, it can limit the inflammatory response, which can be cardio-damaging.[14]

Immunomodulation

PBRs (TSPOs) have many actions on immune cells including modulation of oxidative bursts by neutrophils and macrophages, inhibition of the proliferation of lymphoid cells and secretion of cytokines by macrophages.[15] Expression of TSPO is also linked to inflammatory responses that occur after ischemia-reperfusion injury, following brain injury, and in some neurodegenerative diseases.[citation needed]

Increased expression of TSPO is linked to the inflammatory responses in the heart that may cause myocarditis, which can lead to myocardial necrosis. TSPO is present in mast cells and macrophages, indicating its role in the immune system.[13] Oxidative stress is a strong contributing factor to cardiovascular disease, and often occurs because of inflammation caused by ischemia reperfusion injury.[16] Coxsackievirus B3 (CVB3) causes immune cells CD11b+ (present on macrophages) to stimulate inflammatory infiltration. Functionally, CD11b+ regulates leukocyte adhesion and migration to regulate the inflammatory response.[14] Following infection, CD11b+ is up-regulated, activating these immune responses, which then activate an increased expression of TSPO. These immune cells can cause myocarditis which can progress to dilated cardiomyopathy and heart failure.[14]

Apoptosis

Ligands of TSPO have been shown to induce apoptosis in human colorectal cancer cells.[citation needed] In lymphatic tissues, TSPO modulates apoptosis of thymocytes via reduction of mitochondrial transmembrane potential.[17]

Stress adaptation

TSPO in the basal land plant Physcomitrella patens, a moss, is essential for adaptation to salt stress.[18]

Tissue distribution

TSPO is found in many regions of the body including the human iris/ciliary-body.[19] Other tissues include the heart, liver, adrenal and testis, as well as hemopoietic and lymphatic cells.[20] "Peripheral" benzodiazepine receptors are also found in the brain, although only at around a quarter the expression levels of the "central" benzodiazepine receptors located at the plasma membrane.[21]

Therapeutic applications

TSPO has been shown to be involved in a number of processes such as inflammation,[22] and TSPO ligands may be useful anti-cancer drugs.[23][24]

Pharmacological activation of TSPO has been observed to be a potent stimulator of steroid biosynthesis [25][26] including neuroactive steroids such as allopregnanolone in the brain, which exert anxiolytic properties.[27] Thus, TSPO ligands such as emapunil (XBD-173) or alpidem have been proposed to be useful as potential anxiolytics which may have less addiction-based side effects than traditional benzodiazepine-type drugs.,[28][29][30][31] though toxicity side-effects remain a significant barrier in drug development.[32]

A 2013 study led by researchers from USC Davis School of Gerontology showed that TSPO ligands can prevent and at least partially correct abnormalities present in a mouse model of Alzheimer's disease.[33]

TSPO as a biomarker is a newly discovered non-invasive procedure, and has also been linked as a biomarker for other cardiovascular related diseases including: myocardial infarction (due to ischemic reperfusion), cardiac hypertrophy, atherosclerosis, arrhythmias, and large vessel vasculitis.[16] TSPO can be used as a biomarker to detect the presence and severity of inflammation in the heart and atherosclerotic plaques.[14]Inhibiting the over-production of TSPO can lead to a reduced incidence of arrhythmias which are most often caused by ischemia reperfusion injury.[16] TSPO ligands are used as a therapy after ischemia reperfusion injury to preserve the action potentials in cardiac tissue and restore normal electrical activity of the heart.[13] Higher levels of TSPO are present in those with heart disease, a change that is more common in men than women because testosterone worsens the inflammation causing permanent damage to the heart.[14]

The first high-resolution 3D solution structure of mammalian (mouse) translocator protein (TSPO) in a complex with its diagnostic PK11195 ligand was determined by means of NMR spectroscopy techniques by scientists from the Max-Planck Institute for Biophysical Chemistry in Goettingen in Germany in March 2014 (Jaremko et al., 2014) and has a PDB id: 2MGY. Obtained high-resolution clearly confirms a helical character of a protein and its complex with a diagnostic ligand in solution. The 3D structure of the mTSPO-PK11195 complex comprises five transmembrane α-helices (TM1 to TM5) that tightly pack together in the clockwise order TM1-TM2-TM5-TM4-TM3 (cytosol view). The mammalian TSPO in a complex with diagnostic ligand is nomomeric. The loop located in between TM1 and TM2 helices closes the entrance to the space between helices in which are bound with PK11195 molecule. Site-directed mutagenesis studies of mTSPO revealed that region important for PK11195 binding comprise amino acids from 41 to 51, because the deletion of this region resulted in the decrease in PK11195 binding (Fan et al., 2012).

The mammalian TSPO in a complex with the diagnostic ligand PK11195 is monomeric.[34][35]

Imaging

Ligands of the TSPO are very useful for imaging of inflammation. For example, the radioligand [3H]-PK-11195 has been used in receptor autoradiography to study neuroinflammation following brain injury. The affinity of [11C]-PBR28 depends on a single polymorphism (rs6971) in the TSPO gene.[36]

Measuring microglial activation in vivo is possible using PET imaging and radioligands binding to 18 kDa translocator protein (TSPO).[37] Activation can be meassured using the PET tracer (R)-[11C]PK11195 and others like PBR28 are under research.[38]

Selective ligands

Agonists

  • YL-IPA08
  • Ro5-4864 - original ligand with which TSPO receptor was characterised, now less used due to inter-species differences in binding affinity. Sedative yet also convulsant and anxiogenic in mice.[39]
Peptides
  • Anthralin - 16kDa polypeptide, binds to both TSPO receptor and dihydropyridine-sensitive calcium channels with high affinity.[40]
  • Diazepam binding inhibitor (DBI) - 11kDa neuropeptide, potent agonist for TSPO receptor and stimulates steroidogenesis in vivo,[41][42][43] also negative allosteric modulator of benzodiazepine-sensitive GABAA receptors.[44]
  • DBI 17-50 fragment - active processing product of DBI
Non-peptides

Antagonists

  • PK-11195 - potent and selective antagonist for both rat and human forms of TSPO.

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000100300 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000041736 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (August 2006). "Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function". Trends Pharmacol. Sci. 27 (8): 402–9. doi:10.1016/j.tips.2006.06.005. PMID 16822554. 
  6. ^ Chang YJ, McCabe RT, Rennert H, Budarf ML, Sayegh R, Emanuel BS, Skolnick P, Strauss JF (1992). "The human "peripheral-type" benzodiazepine receptor: regional mapping of the gene and characterization of the receptor expressed from cDNA". DNA Cell Biol. 11 (6): 471–80. doi:10.1089/dna.1992.11.471. PMID 1326278. 
  7. ^ Riond J, Mattei MG, Kaghad M, Dumont X, Guillemot JC, Le Fur G, Caput D, Ferrara P (January 1991). "Molecular cloning and chromosomal localization of a human peripheral-type benzodiazepine receptor". Eur. J. Biochem. 195 (2): 305–11. doi:10.1111/j.1432-1033.1991.tb15707.x. PMID 1847678. 
  8. ^ Bogan RL, Davis TL, Niswender GD (April 2007). "Peripheral-type benzodiazepine receptor (PBR) aggregation and absence of steroidogenic acute regulatory protein (StAR)/PBR association in the mitochondrial membrane as determined by bioluminescence resonance energy transfer (BRET)". J. Steroid Biochem. Mol. Biol. 104 (1–2): 61–7. doi:10.1016/j.jsbmb.2006.10.007. PMID 17197174. 
  9. ^ Casellas P, Galiegue S, Basile AS (2002). "Peripheral benzodiazepine receptors and mitochondrial function". Neurochem Int. 40 (6): 475–86. doi:10.1016/S0197-0186(01)00118-8. PMID 11850104. 
  10. ^ Lacapère JJ, Papadopoulos V (September 2003). "Peripheral-type benzodiazepine receptor: structure and function of a cholesterol-binding protein in steroid and bile acid biosynthesis". Steroids. 68 (7–8): 569–585. doi:10.1016/s0039-128x(03)00101-6. PMID 12957662. 
  11. ^ Morohaku K, Pelton SH, Daugherty DJ, Ronald Butler W, Deng W, Selvaraj V (2013). "Translocator Protein/Peripheral Benzodiazepine Receptor Is Not Required for Steroid Hormone Biosynthesis". Endocrinology. 155 (1): 89–97. doi:10.1210/en.2013-1556. PMC 3868810Freely accessible. PMID 24174323. 
  12. ^ Midzak A, Papadopoulos V (Sep 2014). "Binding domain-driven intracellular trafficking of sterols for synthesis of steroid hormones, bile acids and oxysterols". Traffic. 15 (9): 895–914. doi:10.1111/tra.12177. PMID 24890942. 
  13. ^ a b c Qi X, Xu J, Wang F, Xiao J (2012). "Translocator protein (18 kDa): a promising therapeutic target and diagnostic tool for cardiovascular diseases" (PDF). Oxid Med Cell Longev. 2012: 162934. doi:10.1155/2012/162934. PMC 3516045Freely accessible. PMID 23251719. 
  14. ^ a b c d e Fairweather D, Coronado MJ, Garton AE, Dziedzic JL, Bucek A, Cooper LT, Brandt JE, Alikhan FS, Wang H, Endres CJ, Choi J, Pomper MG, Guilarte TR (March 2014). "Sex differences in translocator protein 18 kDa (TSPO) in the heart: implications for imaging myocardial inflammation". J Cardiovasc Transl Res. 7 (2): 192–202. doi:10.1007/s12265-013-9538-0. PMC 3951973Freely accessible. PMID 24402571. 
  15. ^ Pawlikowski M (1993). "Immunomodulating effects of peripherally acting benzodiazepines". New York: In Peripheral Benzodiazepine Receptors. Academic press. pp. 125–135. 
  16. ^ a b c Batarseh A, Papadopoulos V (2010). "Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states" (PDF). Mol. Cell. Endocrinol. 327: 1–12. doi:10.1016/j.mce.2010.06.013. PMC 2922062Freely accessible. PMID 20600583. 
  17. ^ Tanimoto Y, Onishi Y, Sato Y, Kizaki H (February 1999). "Benzodiazepine receptor agonists modulate thymocyte apoptosis through reduction of the mitochondrial transmembrane potential". Jpn. J. Pharmacol. 79 (2): 177–83. doi:10.1254/jjp.79.177. PMID 10202853. 
  18. ^ Frank W, Baar KM, Qudeimat E, Woriedh M, Alawady A, Ratnadewi D, Gremillon L, Grimm B, Reski R (September 2007). "A mitochondrial protein homologous to the mammalian peripheral-type benzodiazepine receptor is essential for stress adaptation in plants". Plant J. 51 (6): 1004–18. doi:10.1111/j.1365-313X.2007.03198.x. PMID 17651369. 
  19. ^ Valtier D, Malgouris C, Gilbert JC, Guicheney P, Uzan A, Gueremy C, Le Fur G, Saraux H, Meyer P (June 1987). "Binding sites for a peripheral type benzodiazepine antagonist ([3H]PK 11195) in human iris". Neuropharmacology. 26 (6): 549–52. doi:10.1016/0028-3908(87)90146-8. PMID 3037422. 
  20. ^ Woods MG, Williams DC (1996). Multiple forms and locations for the peripheral-type benzodiazepine receptor. Biochemical Pharmacology. 52. pp. 1805–1814. doi:10.1016/S0006-2952(96)00558-8. PMID 8951338. 
  21. ^ Marangos PJ, Patel J, Boulenger JP, Clark-Rosenberg R (July 1982). "Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro 5-4864". Molecular Pharmacology. 22 (1): 26–32. PMID 6289073. 
  22. ^ Chen MK, Guilarte TR (April 2008). "Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair". Pharmacology & Therapeutics. 118 (1): 1–17. doi:10.1016/j.pharmthera.2007.12.004. PMC 2453598Freely accessible. PMID 18374421. 
  23. ^ Santidrián AF, Cosialls AM, Coll-Mulet L, Iglesias-Serret D, de Frias M, González-Gironès DM, Campàs C, Domingo A, Pons G, Gil J (December 2007). "The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells". Haematologica. 92 (12): 1631–8. doi:10.3324/haematol.11194. PMID 18055986. 
  24. ^ Kugler W, Veenman L, Shandalov Y, Leschiner S, Spanier I, Lakomek M, Gavish M (2008). "Ligands of the mitochondrial 18 kDa translocator protein attenuate apoptosis of human glioblastoma cells exposed to erucylphosphohomocholine". Cellular Oncology. 30 (5): 435–50. PMID 18791274. 
  25. ^ Veenman L, Papadopoulos V, Gavish M (2007). "Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response". Current Pharmaceutical Design. 13 (23): 2385–405. doi:10.2174/138161207781368710. PMID 17692008. 
  26. ^ Falchi AM, Battetta B, Sanna F, Piludu M, Sogos V, Serra M, Melis M, Putzolu M, Diaz G (August 2007). "Intracellular cholesterol changes induced by translocator protein (18 kDa) TSPO/PBR ligands". Neuropharmacology. 53 (2): 318–29. doi:10.1016/j.neuropharm.2007.05.016. PMID 17631921. 
  27. ^ Farb DH, Ratner MH (October 2014). "Targeting the modulation of neural circuitry for the treatment of anxiety disorders". Pharmacol Rev. 66 (4): 1002–1032. doi:10.1124/pr.114.009126. PMID 25237115. 
  28. ^ Mealy NE, Bayés M, Lupone B (2006). "Psychiatric Disorders". Drugs of the Future. 31 (3): 259. 
  29. ^ Da Settimo F, Simorini F, Taliani S, La Motta C, Marini AM, Salerno S, Bellandi M, Novellino E, Greco G, Cosimelli B, Da Pozzo E, Costa B, Simola N, Morelli M, Martini C (September 2008). "Anxiolytic-like effects of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides by modulation of translocator protein promoting neurosteroid biosynthesis". Journal of Medicinal Chemistry. 51 (18): 5798–806. doi:10.1021/jm8003224. PMID 18729350. 
  30. ^ Taliani S, Da Settimo F, Da Pozzo E, Chelli B, Martini C (September 2009). "Translocator Protein Ligands as Promising Therapeutic Tools for Anxiety Disorders". Current Medicinal Chemistry. 16 (26): 3359–80. doi:10.2174/092986709789057653. PMID 19548867. 
  31. ^ Rupprecht R, Rammes G, Eser D, Baghai TC, Schüle C, Nothdurfter C, Troxler T, Gentsch C, Kalkman HO, Chaperon F, Uzunov V, McAllister KH, Bertaina-Anglade V, La Rochelle CD, Tuerck D, Floesser A, Kiese B, Schumacher M, Landgraf R, Holsboer F, Kucher K (June 2009). "Translocator Protein (18 kD) as Target for Anxiolytics Without Benzodiazepine-Like Side Effects". Science. 325 (5939): 490–3. doi:10.1126/science.1175055. PMID 19541954. 
  32. ^ Skolnick P (November 2012). "Anxioselective anxiolytics: on a quest for the Holy Grail". Trends Pharmacol Sci. 33 (11): 611–620. doi:10.1016/j.tips.2012.08.003. PMC 3482271Freely accessible. PMID 22981367. 
  33. ^ Barron, A. M.; Garcia-Segura, L. M.; Caruso, D.; Jayaraman, A.; Lee, J. -W.; Melcangi, R. C.; Pike, C. J. (2013). "Ligand for Translocator Protein Reverses Pathology in a Mouse Model of Alzheimer's Disease". The Journal of Neuroscience. 33 (20): 8891–8897. doi:10.1523/JNEUROSCI.1350-13.2013. PMC 3733563Freely accessible. PMID 23678130. 
  34. ^ Jaremko L, Jaremko M, Giller K, Becker S, Zweckstetter M (March 2014). "Structure of the mitochondrial translocator protein in complex with a diagnostic ligand". Science. 343 (6177): 1363–6. doi:10.1126/science.1248725. PMC 5650047Freely accessible. PMID 24653034. 
  35. ^ Fan J, Lindemann P, Feuilloley MG, Papadopoulos V (May 2012). "Structural and functional evolution of the translocator protein (18 kDa)". Curr. Mol. Med. 12 (4): 369–86. doi:10.2174/156652412800163415. PMID 22364126. 
  36. ^ Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, Stjean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP (October 2011). "An 18-kDa Translocator Protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28". J Cereb Blood Flow Metab. 32 (1): 1–5. doi:10.1038/jcbfm.2011.147. PMC 3323305Freely accessible. PMID 22008728. 
  37. ^ Airas L, Rissanen E, Tuisku J, Rinne J (April 2015). "Microglial Activation Correlates with Disease Progression in Multiple Sclerosis". Neurology. 86 (16 Supplement P4): 167. 
  38. ^ Mirzaei N, Tang SP, Ashworth S, Coello C, Plisson C, Passchier J, Selvaraj V, Tyacke RJ, Nutt DJ, Sastre M (2016). "In vivo imaging of microglial activation by positron emission tomography with [(11)C]PBR28 in the 5XFAD model of Alzheimer's disease". Glia. 64 (6): 993–1006. doi:10.1002/glia.22978. PMID 26959396. 
  39. ^ Pellow S, File SE (July 1984). "Behavioural actions of Ro 5-4864: a peripheral-type benzodiazepine?". Life Sciences. 35 (3): 229–40. doi:10.1016/0024-3205(84)90106-1. PMID 6087055. 
  40. ^ Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, Weizman A (December 1999). "Enigma of the peripheral benzodiazepine receptor". Pharmacological Reviews. 51 (4): 629–50. PMID 10581326. 
  41. ^ Papadopoulos V, Amri H, Boujrad N, Cascio C, Culty M, Garnier M, Hardwick M, Li H, Vidic B, Brown AS, Reversa JL, Bernassau JM, Drieu K (January 1997). "Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis". Steroids. 62 (1): 21–8. doi:10.1016/S0039-128X(96)00154-7. PMID 9029710. 
  42. ^ Costa E, Auta J, Guidotti A, Korneyev A, Romeo E (June 1994). "The pharmacology of neurosteroidogenesis". The Journal of Steroid Biochemistry and Molecular Biology. 49 (4–6): 385–9. doi:10.1016/0960-0760(94)90284-4. PMID 8043504. 
  43. ^ Garnier M, Boujrad N, Ogwuegbu SO, Hudson JR, Papadopoulos V (September 1994). "The polypeptide diazepam-binding inhibitor and a higher affinity mitochondrial peripheral-type benzodiazepine receptor sustain constitutive steroidogenesis in the R2C Leydig tumor cell line". The Journal of Biological Chemistry. 269 (35): 22105–12. PMID 8071335. 
  44. ^ Bormann J, Ferrero P, Guidotti A, Costa E (1985). "Neuropeptide modulation of GABA receptor C1- channels". Regulatory Peptides. Supplement. 4: 33–8. doi:10.1016/0167-0115(85)90215-0. PMID 2414820. 

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TspO/MBR family Provide feedback

Tryptophan-rich sensory protein (TspO) is an integral membrane protein that acts as a negative regulator of the expression of specific photosynthesis genes in response to oxygen/light [1]. It is involved in the efflux of porphyrin intermediates from the cell. This reduces the activity of coproporphyrinogen III oxidase, which is thought to lead to the accumulation of a putative repressor molecule that inhibits the expression of specific photosynthesis genes. Several conserved aromatic residues are necessary for TspO function: they are thought to be involved in binding porphyrin intermediates [3]. In [2] the rat mitochondrial peripheral benzodiazepine receptor (MBR) was shown to not only retain its structure within a bacterial outer membrane, but also to be able to functionally substitute for TspO in TspO- mutants, and to act in a similar manner to TspO in its in situ location: the outer mitochondrial membrane. The biological significance of MBR remains unclear, however. It is thought to be involved in a variety of cellular functions, including cholesterol transport in steroidogenic tissues.

Literature references

  1. Yeliseev AA, Kaplan S; , J Biol Chem 1995;270:21167-21175.: A sensory transducer homologous to the mammalian peripheral-type benzodiazepine receptor regulates photosynthetic membrane complex formation in Rhodobacter sphaeroides 2.4.1. PUBMED:7673149 EPMC:7673149

  2. Yeliseev AA, Krueger KE, Kaplan S; , Proc Natl Acad Sci U S A 1997;94:5101-5106.: A mammalian mitochondrial drug receptor functions as a bacterial oxygen sensor. PUBMED:9144197 EPMC:9144197

  3. Yeliseev AA, Kaplan S; , J Biol Chem 2000;275:5657-5667.: TspO of rhodobacter sphaeroides. A structural and functional model for the mammalian peripheral benzodiazepine receptor. PUBMED:10681549 EPMC:10681549


Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR004307

Members of this group are involved in transmembrane signalling. In both prokaryotes and mitochondria they are localized to the outer membrane, and have been shown to bind and transport dicarboxylic tetrapyrrole intermediates of the haem biosynthetic pathway [PUBMED:1373486, PUBMED:7673149]. They are associated with the major outer membrane porins (in prokaryotes) and with the voltage-dependent anion channel (in mitochondria) [PUBMED:8114671].

Rhodobacter sphaeroides TspO (previously CrtK) is involved in signal transduction, functioning as a negative regulator of the expression of some photosynthesis genes (PpsR/AppA repressor/antirepressor regulon). This down-regulation is believed to be in response to oxygen levels. TspO works through (or modulates) the PpsR/AppA system and acts upstream of the site of action of these regulatory proteins [PUBMED:11591680]. It has been suggested that the TspO regulatory pathway works by regulating the efflux of certain tetrapyrrole intermediates of the haem/bacteriochlorophyll biosynthetic pathways in response to the availability of molecular oxygen, thereby causing the accumulation of a biosynthetic intermediate that serves as a corepressor for the regulated genes [PUBMED:10409680]. A homologue of the TspO protein in Rhizobium meliloti (Sinorhizobium meliloti) is involved in regulating expression of the ndi locus in response to stress conditions [PUBMED:11097914]. There is evidence that the S. meliloti TspO acts through, or in addition to, the FixL regulatory system.

In animals, translocator protein (TSPO), previously known as peripheral-type benzodiazepine receptor (PBR, MBR) is a mitochondrial protein (located in the outer mitochondrial membrane) where it forms a complex with several proteins of the mitochondrial permeability transition pore (MPTP). TSPO is involved in multiple processes, including regulation of cell death, cholesterol transport and steroid biosynthesis, mitochondrial respiration and oxidation and mitochondrial protein import [PUBMED:23518318, PUBMED:22364127].

These observations suggest that fundamental aspects of this receptor and the downstream signal transduction pathway are conserved in bacteria and higher eukaryotic mitochondria. The alpha-3 subdivision of the purple bacteria is considered to be a likely source of the endosymbiont that ultimately gave rise to the mitochondrion. Therefore, it is possible that the mammalian PBR remains both evolutionarily and functionally related to the TspO of R. sphaeroides.

Gene Ontology

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NCBI
(12189)
Meta
(1229)
RP15
(1072)
RP35
(2704)
RP55
(4127)
RP75
(5536)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_1882 (release 6.4)
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Mifsud W
Number in seed: 517
Number in full: 4161
Average length of the domain: 144.00 aa
Average identity of full alignment: 27 %
Average coverage of the sequence by the domain: 81.49 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.8 21.8
Trusted cut-off 21.8 21.8
Noise cut-off 21.7 21.7
Model length: 135
Family (HMM) version: 15
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the TspO_MBR domain has been found. There are 21 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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