Structural Integrity of the A147T Polymorph of Mammalian TSPO

Jaremko, Mariusz; Jaremko, Łukasz; Giller, Karin; Becker, Stefan; Zweckstetter, Markus

doi:10.1002/cbic.201500217

Cited by 33 publications

(46 citation statements)

References 42 publications

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“…Twom ajor ligand-binding sites in the structure of mammalian TSPO have hitherto been identified. The binding site observed in the 3D structure of the mTSPO/(R)-PK11195 complex [18,23] is common to severalr adioligands according to competition experiments. [27] The second binding site is also located neart he cytosolic side of the membrane and is formed by residues 147-159 in transmembrane region five.…”

Section: Discussionmentioning

confidence: 99%

Conformational Flexibility in the Transmembrane Protein TSPO

Jaremko

Giller

et al. 2015

Chemistry A European J

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The translocator protein TSPO is an integral membrane protein that interacts with a large variety of endogenous ligands such as cholesterol and porphyrins, and is also the target for several small molecules with substantial in vivo efficacy. In complex with the TSPO-specific radioligand (R)-PK11195, TSPO folds into a rigid five-helix bundle. However, little is known about the structure and dynamics of TSPO in the absence of high-affinity ligands. Using NMR spectroscopy we show that TSPO exchanges between multiple conformations in the absence of (R)-PK11195. Extensive motions on time scales from pico-to-microseconds occur across all of TSPO's primary sequence and lead to a loss of stable tertiary interactions and the local unfolding of helical structure in the vicinity of the ligand-binding site. The flexible nature of TSPO highlights the importance of conformational plasticity in integral membrane proteins.

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Section: Discussionmentioning

confidence: 99%

Conformational Flexibility in the Transmembrane Protein TSPO

Jaremko

Giller

et al. 2015

Chemistry A European J

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“…Jaremko and colleagues have argued that the differences arise from crystal packing effects. 44,48 However, the published crystal structures were determined from at least five different crystal forms, each with unique differing packing arrangements and intermolecular contacts, yet all yield the same overall tertiary structure. Thus, it is unlikely that “crystal packing” is the cause of these major discrepancies.…”

Section: Crystal and Nmr Structures: Similarities And Differencesmentioning

confidence: 99%

Translocator Protein 18 kDa (TSPO): An Old Protein with New Functions?

et al. 2016

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Translocator protein 18 kDa (TSPO) was previously known as the peripheral benzodiazepine receptor (PBR) in eukaryotes, where it is mainly localized to the mitochondrial outer membrane. Considerable evidence indicates that it plays regulatory roles in steroidogenesis and apoptosis and is involved in various human diseases, such as metastatic cancer, Alzheimer’s and Parkinson’s disease, inflammation, and anxiety disorders. Ligands of TSPO are widely used as diagnostic tools and treatment options, despite there being no clear understanding of the function of TSPO. An ortholog in the photosynthetic bacterium Rhodobacter was independently discovered as the tryptophan-rich sensory protein (TspO) and found to play a role in the response to changes in oxygen and light conditions that regulate photosynthesis and respiration. As part of this highly conserved protein family found in all three kingdoms, the rat TSPO is able to rescue the knockout phenotype in Rhodobacter, indicating functional as well as structural conservation. Recently, a major breakthrough in the field was achieved: the determination of atomic-resolution structures of TSPO from different species by several independent groups. This now allows us to reexamine the function of TSPO with a molecular perspective. In this review, we focus on recently determined structures of TSPO and their implications for potential functions of this ubiquitous multifaceted protein. We suggest that TSPO is an ancient bacterial receptor/stress sensor that has developed additional interactions, partners, and roles in its mitochondrial outer membrane environment in eukaryotes.

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“…An 18 kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. It has been suggested that in the cases of PBR28 and other second-generation ligands, A147T mTSPO might no longer be able to retain the same structural and dynamic profile as the wild-type protein and thus binds these ligands with lower affinity [ 66 ]. Nonetheless, this polymorphism does not affect affinity for PK 11195 [ 67 ].…”

Section: Tetrapyrroles Including Protoporphyrins Such As Ppix Asmentioning

confidence: 99%

Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

Veenman

Vainshtein

Yasin

et al. 2016

IJMS

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The 18 kDa translocator protein (TSPO) is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO’s importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles’ membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships.

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Structural Integrity of the A147T Polymorph of Mammalian TSPO

Cited by 33 publications

References 42 publications

Conformational Flexibility in the Transmembrane Protein TSPO

Conformational Flexibility in the Transmembrane Protein TSPO

Translocator Protein 18 kDa (TSPO): An Old Protein with New Functions?

Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

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