Structure and activity of tryptophan-rich TSPO proteins

Youzhong Guo; Ravi C. Kalathur; Qun Liu; Brian Kloss; Renato Bruni; Christopher Ginter; Edda Kloppmann; Burkhard Rost; Wayne A. Hendrickson

doi:10.1126/science.aaa1534

Structure and activity of tryptophan-rich TSPO proteins

Youzhong Guo, Ravi C. Kalathur, Qun Liu, Brian Kloss, Renato Bruni, Christopher Ginter, Edda Kloppmann, Burkhard Rost, Wayne A. Hendrickson

Informatics 12 - Chair of Bioinformatics

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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 A 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.

Original language	English
Pages (from-to)	551-555
Number of pages	5
Journal	Science
Volume	347
Issue number	6221
DOIs	https://doi.org/10.1126/science.aaa1534
State	Published - 30 Jan 2015

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title = "Structure and activity of tryptophan-rich TSPO proteins",

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 A 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.",

author = "Youzhong Guo and Kalathur, {Ravi C.} and Qun Liu and Brian Kloss and Renato Bruni and Christopher Ginter and Edda Kloppmann and Burkhard Rost and Hendrickson, {Wayne A.}",

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T1 - Structure and activity of tryptophan-rich TSPO proteins

AU - Guo, Youzhong

AU - Kalathur, Ravi C.

AU - Liu, Qun

AU - Kloss, Brian

AU - Bruni, Renato

AU - Ginter, Christopher

AU - Kloppmann, Edda

AU - Rost, Burkhard

AU - Hendrickson, Wayne A.

PY - 2015/1/30

Y1 - 2015/1/30

N2 - 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 A 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.

AB - 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 A 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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VL - 347

SP - 551

EP - 555

JO - Science

JF - Science

IS - 6221

ER -

Structure and activity of tryptophan-rich TSPO proteins

Abstract

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