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Structure and activity of tryptophan-rich TSPO proteins

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Science  30 Jan 2015:
Vol. 347, Issue 6221, pp. 551-555
DOI: 10.1126/science.aaa1534

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Structural clues to protein function

Translocator protein (TSPO) is a mitochondrial membrane protein thought to transport cholesterol and porphyrins. Its detailed function remains unclear, but interest in it is high because TSPO is involved in a variety of human diseases. Two papers now present crystal structures of bacterial TSPOs. Li et al. show that a mutant that mimics a human single polymorphism associated with psychiatric disorders has structural changes in a region implicated in cholesterol binding. Guo et al. suggest that TSPO may be more than a transporter. They show how it catalyzes the degradation of porphyrins, a function that could be important in protection against oxidative stress.

Science, this issue p. 555, p. 551

Abstract

Translocator proteins (TSPOs) bind steroids and porphyrins, and they are implicated in many human diseases, for which they serve as biomarkers and therapeutic targets. TSPOs have tryptophan-rich sequences that are highly conserved from bacteria to mammals. Here we report crystal structures for Bacillus cereus TSPO (BcTSPO) down to 1.7 Å resolution, including a complex with the benzodiazepine-like inhibitor PK11195. We also describe BcTSPO-mediated protoporphyrin IX (PpIX) reactions, including catalytic degradation to a previously undescribed heme derivative. We used structure-inspired mutations to investigate reaction mechanisms, and we showed that TSPOs from Xenopus and man have similar PpIX-directed activities. Although TSPOs have been regarded as transporters, the catalytic activity in PpIX degradation suggests physiological importance for TSPOs in protection against oxidative stress.

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