Protein Structure. Crystal Structures of Translocator Protein (TSPO) and Mutant Mimic of a Human Polymorphism

Overview

Journal Science

Specialty Science

Date 2015 Jan 31

PMID 25635101

Citations 80

Authors

Fei Li

Jian Liu

Yi Zheng

R Michael Garavito

Shelagh Ferguson-Miller

Affiliations

Soon will be listed here.

Abstract

The 18-kilodalton translocator protein (TSPO), proposed to be a key player in cholesterol transport into mitochondria, is highly expressed in steroidogenic tissues, metastatic cancer, and inflammatory and neurological diseases such as Alzheimer's and Parkinson's. TSPO ligands, including benzodiazepine drugs, are implicated in regulating apoptosis and are extensively used in diagnostic imaging. We report crystal structures (at 1.8, 2.4, and 2.5 angstrom resolution) of TSPO from Rhodobacter sphaeroides and a mutant that mimics the human Ala(147)→Thr(147) polymorphism associated with psychiatric disorders and reduced pregnenolone production. Crystals obtained in the lipidic cubic phase reveal the binding site of an endogenous porphyrin ligand and conformational effects of the mutation. The three crystal structures show the same tightly interacting dimer and provide insights into the controversial physiological role of TSPO and how the mutation affects cholesterol binding.

Citing Articles

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References

Rupprecht R, Papadopoulos V, Rammes G, Baghai T, Fan J, Akula N . Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010; 9(12):971-88. DOI: 10.1038/nrd3295. View

Morohaku K, Pelton S, Daugherty D, Butler W, Deng W, Selvaraj V . Translocator protein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis. Endocrinology. 2013; 155(1):89-97. PMC: 3868810. DOI: 10.1210/en.2013-1556. View

Lacapere J, Papadopoulos V . Peripheral-type benzodiazepine receptor: structure and function of a cholesterol-binding protein in steroid and bile acid biosynthesis. Steroids. 2003; 68(7-8):569-85. DOI: 10.1016/s0039-128x(03)00101-6. View

Dutzler R, Schirmer T, Karplus M, Fischer S . Translocation mechanism of long sugar chains across the maltoporin membrane channel. Structure. 2002; 10(9):1273-84. DOI: 10.1016/s0969-2126(02)00811-0. View

Fan J, Papadopoulos V . Evolutionary origin of the mitochondrial cholesterol transport machinery reveals a universal mechanism of steroid hormone biosynthesis in animals. PLoS One. 2013; 8(10):e76701. PMC: 3790746. DOI: 10.1371/journal.pone.0076701. View

Costa B, Pini S, Martini C, Abelli M, Gabelloni P, Landi S . Ala147Thr substitution in translocator protein is associated with adult separation anxiety in patients with depression. Psychiatr Genet. 2009; 19(2):110-1. DOI: 10.1097/YPG.0b013e32832080f6. View

Gatliff J, Campanella M . The 18 kDa translocator protein (TSPO): a new perspective in mitochondrial biology. Curr Mol Med. 2012; 12(4):356-68. DOI: 10.2174/1566524011207040356. View

Hardwick M, Fertikh D, Culty M, Li H, Vidic B, Papadopoulos V . Peripheral-type benzodiazepine receptor (PBR) in human breast cancer: correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol. Cancer Res. 1999; 59(4):831-42. View

Farges R, Shire D, Caput D, Le Fur G, Ferrara P . Site-directed mutagenesis of the peripheral benzodiazepine receptor: identification of amino acids implicated in the binding site of Ro5-4864. Mol Pharmacol. 1994; 46(6):1160-7. View

10.

Yeliseev A, KRUEGER K, Kaplan S . A mammalian mitochondrial drug receptor functions as a bacterial "oxygen" sensor. Proc Natl Acad Sci U S A. 1997; 94(10):5101-6. PMC: 24638. DOI: 10.1073/pnas.94.10.5101. View

11.

Fan J, Lindemann P, Feuilloley M, Papadopoulos V . Structural and functional evolution of the translocator protein (18 kDa). Curr Mol Med. 2012; 12(4):369-86. DOI: 10.2174/1566524011207040369. View

12.

Korkhov V, Sachse C, Short J, Tate C . Three-dimensional structure of TspO by electron cryomicroscopy of helical crystals. Structure. 2010; 18(6):677-87. PMC: 2911597. DOI: 10.1016/j.str.2010.03.001. View

13.

Bird J, Izquierdo-Garcia D, Davies J, Rudd J, Probst K, Figg N . Evaluation of translocator protein quantification as a tool for characterising macrophage burden in human carotid atherosclerosis. Atherosclerosis. 2010; 210(2):388-91. PMC: 2884178. DOI: 10.1016/j.atherosclerosis.2009.11.047. View

14.

Qin L, Hiser C, Mulichak A, Garavito R, Ferguson-Miller S . Identification of conserved lipid/detergent-binding sites in a high-resolution structure of the membrane protein cytochrome c oxidase. Proc Natl Acad Sci U S A. 2006; 103(44):16117-22. PMC: 1616942. DOI: 10.1073/pnas.0606149103. View

15.

Li H, Papadopoulos V . Peripheral-type benzodiazepine receptor function in cholesterol transport. Identification of a putative cholesterol recognition/interaction amino acid sequence and consensus pattern. Endocrinology. 1998; 139(12):4991-7. DOI: 10.1210/endo.139.12.6390. View

16.

Costa B, Pini S, Gabelloni P, Da Pozzo E, Abelli M, Lari L . The spontaneous Ala147Thr amino acid substitution within the translocator protein influences pregnenolone production in lymphomonocytes of healthy individuals. Endocrinology. 2009; 150(12):5438-45. DOI: 10.1210/en.2009-0752. View

17.

Zeno S, Veenman L, Katz Y, Bode J, Gavish M, Zaaroor M . The 18 kDa mitochondrial translocator protein (TSPO) prevents accumulation of protoporphyrin IX. Involvement of reactive oxygen species (ROS). Curr Mol Med. 2012; 12(4):494-501. DOI: 10.2174/1566524011207040494. View

18.

Scarf A, Luus C, Da Pozzo E, Selleri S, Guarino C, Martini C . Evidence for complex binding profiles and species differences at the translocator protein (TSPO) (18 kDa). Curr Mol Med. 2012; 12(4):488-93. DOI: 10.2174/156652412800163460. View

19.

Owen D, Yeo A, Gunn R, Song K, Wadsworth G, Lewis A . An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2011; 32(1):1-5. PMC: 3323305. DOI: 10.1038/jcbfm.2011.147. View

20.

Esser C, Martin W, Dagan T . The origin of mitochondria in light of a fluid prokaryotic chromosome model. Biol Lett. 2007; 3(2):180-4. PMC: 2375920. DOI: 10.1098/rsbl.2006.0582. View