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Research Themes Cell biology

Design and Evolution: Unveiling Translocator Proteins

SBKB [doi:10.1038/sbkb.2015.16]
Featured Article - June 2015
Short description: Structural and functional analyses provide new insights on the physiological roles of TSPOs.


Cartoon representation of the Bacillus cereus TSPO dimer in complex with PK-11195, shown in sticks (PDB 4RYI). Figure from ref. 1 , reprinted with permission from AAAS.

Translocator proteins (TSPOs) are ∼18 kDa transmembrane proteins, remarkably conserved in sequence and function from bacteria to humans. TSPOs have been implicated in neurological disorders, cardiovascular diseases and cancer, but their exact physiological roles have remained elusive. They were originally identified as peripheral benzodiazepine receptors in mammals, with a prokaryotic ortholog, tryptophan-rich sensory protein TspO, described later.

In eukaryotes, TSPOs seem to have diverse functions—most notably the transport of cholesterol across mitochondrial membranes for steroid biosynthesis—though TSPO knockout mice did not display defects in steroid biosynthesis. Eukaryotic TSPOs are also implicated in transport of porphyrins (e.g. heme and protoporphyrin IX (PpIX)) and, in support of their evolutionary conservation, bacterial TSPOs have been shown to catalyze the photo-oxidative degradation of PpIX.

Two independent groups have now reported crystal structures of bacterial TSPOs, providing important clues to decipher their functions. Ferguson-Miller and colleagues (with support from PSI CSMP) described the structures of TSPO from Rhodobacter sphaeroides in its apo form (PDB 4UC3), with a mutation equivalent to a human polymorphism (A147T) associated with neurological disorders (PDB 4UC2), and in complex with PpIX (PDB 4UC1); all structures showed TSPO forming a dimer. Hendrickson and colleagues (PSI NYCOMPS) have solved structures of the Bacillus cereus TSPO apo (PDB 4RYQ, monomer), and in complex with the benzodiazepine-like drug PK-11195 (PDB 4RYI, dimer).

A previous NMR structure of mouse TSPO featured five transmembrane helices. The new crystal structures confirm this observation, but also show the helices in a different overall organization. In addition, Ferguson-Miller and colleagues showed that the mutant bearing the human polymorphism mutation impairs cholesterol and PpIX binding. Hendrickson and colleagues tested a similar mutation and showed that it impairs TSPO's ability to catalyze PpIX degradation.

The dimer interface seen in some of the crystal structures seems unable to form a translocation pathway. However, Ferguson-Miller and colleagues found several monoolein molecules bound to crevices on the protein surface, hinting at a cholesterol transport along TSPO's external surface, with the possible involvement of partner proteins. Hendrickson and colleagues showed that TSPO can degrade PpIX to a novel heme derivative, bilindigin, suggesting a protective function against oxidative stress.

Although many questions are yet to be fully addressed, these new studies provide a basis for elucidating the mechanism and physiological roles of TSPO.

Cosma Dellisanti

References

  1. F. Li et al. Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism.
    Science. 347, 555-8 (2015). doi:10.1126/science.1260590

  2. Y. Guo et al. Structure and activity of tryptophan-rich TSPO proteins.
    Science. 347, 551-5 (2015). doi:10.1126/science.aaa1534

  3. Ł. Jaremko et al. Structure of the mitochondrial translocator protein in complex with a diagnostic ligand.
    Science. 343, 1363-1366 (2014). doi:10.1126/science.1248725

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