Protein structure. Structure and activity of tryptophan-rich TSPO proteins.

TitleProtein structure. Structure and activity of tryptophan-rich TSPO proteins.
Publication TypeJournal Article
Year of Publication2015
AuthorsGuo, Y, Kalathur, RC, Liu, Q, Kloss, B, Bruni, R, Ginter, C, Kloppmann, E, Rost, B, Hendrickson, WA
JournalScience
Volume347
Issue6221
Pagination551-5
Date Published2015 Jan 30
ISSN1095-9203
KeywordsAmino Acid Sequence, Bacillus cereus, Bacterial Proteins, Binding Sites, Crystallography, X-Ray, Isoquinolines, Ligands, Membrane Transport Proteins, Molecular Sequence Data, Mutant Proteins, Protein Conformation, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Protoporphyrins, Reactive Oxygen Species, Tryptophan
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.

DOI10.1126/science.aaa1534
Alternate JournalScience
PubMed ID25635100
PubMed Central IDPMC4341906
Grant ListGM095315 / GM / NIGMS NIH HHS / United States
GM107462 / GM / NIGMS NIH HHS / United States
R01 GM107462 / GM / NIGMS NIH HHS / United States
U54 GM075026 / GM / NIGMS NIH HHS / United States