Structure of TSPO
Shelagh Ferguson-Miller group (Michigan State University)
Shelagh Ferguson-Miller's group at Michigan State University
determined high-resolution crystal structures of an alpha-helical membrane
protein, the Rhodobacter homolog of mitochondrial translocator protein
18 kDa (TSPO), as well as a mutant form that mimics a human disease-related
polymorphism. TSPO is an ancient conserved protein whose functions in
bacteria and in higher eukaryotes are yet to be clearly defined. It was first
identified as a mitochondrial outer membrane protein that binds
benzodiazepine drugs, but distinct from the GABAA receptor of the central
nervous system. Originally called the peripheral benzodiazepine
receptor (PBR), it was renamed the translocator protein or TSPO, in
recognition of its far-reaching phylogeny and mounting evidence of
involvement in a number of complex normal and abnormal cellular processes
including cholesterol transport, porphyrin transport, inflammation and tumor
progression, as well as in Parkinson's and Alzheimer's diseases. A recently
identified single polymorphism in human TSPO (Ala147Thr) is associated with
anxiety-related diseases, making it a potential target for anxiolytic drugs.
There is also widespread use of TSPO ligands for imaging of brain damage, due
to the consistently high expression of TSPO in regions of neuroinflammation.
TSPO was also discovered in photosynthetic bacteria as a regulator of the
transition between respiration and photosynthesis, an activity that appears
related to its ability to bind and translocate porphyrins. Importantly, a
knock-out of bacterial Rhodobacter sphaeroides can be complemented by
rat TSPO, indicating a highly conserved molecular function. The TSPO
structure is a 5 transmembrane helical bundle, unlike most outer membrane
proteins, which are beta-barrels. The structures also show significant
differences between the wild-type and the Ala139Thr mimic of the human
polymorphyism. The mutant has a more closed conformation and a reduced
affinity for cholesterol and porphyrin, consistent with the human phenotype.
A closely associated dimer was found in three different crystal forms,
implying functional significance, but the tight dimer interface does not
suggest a role in transport as had been proposed. An endogenous porphyrin
ligand was also resolved in the X-ray structures, but no drug or cholesterol
molecules were observed, leaving many unanswered questions regarding the
function of this ancient multifaceted protein.
 |
Figure: Crystal structure of RsTSPO
(4UC1) with an endogenous ligand, a porphyrin (black), in the central cavity of one
monomer of the dimeric protein, represented in a simulated membrane. |
Citation: Fei Li, Jian Liu, Yi Zheng, R. Michael Garavito,
Shelagh Ferguson-Miller, "Crystal structures of translocator protein
(TSPO) and mutant mimic of a human polymorphism," Science 347, 555-558
(2015). DOI: 10.1126/science.1260590
|