Structural and Functional Evolution of the Translocator Protein (18 kDa)

Abstract

Translocator proteins (TSPO) are the products of a family of genes that is evolutionarily conserved from bacteria to humans and expressed in most mammalian tissues and cells. Human TSPO (18 kDa) is expressed at high levels in steroid synthesizing endocrine tissues where it localizes to mitochondria and functions in the first step of steroid formation, the transport of cholesterol into the mitochondria. TSPO expression is elevated in cancerous tissues and during tissue injury, which has lead to the hypothesis that TSPO has roles in apoptosis and the maintenance of mitochondrial integrity. We recently identified a new paralog of Tspo in both the human and mouse. This paralog arose from an ancient gene duplication event before the divergence of the classes aves and mammals, and appears to have specialized tissue-, cell-, and organelle-specific functions. Evidence from the study of TSPO homologs in mammals, bacteria, and plants supports the conclusion that the TSPO family of proteins regulates specialized functions related to oxygenmediated metabolism. In this review, we provide a comprehensive overview of the divergent function and evolutionary origin of Tspo genes in Bacteria, Archaea, and Eukarya domains.

Regulation of the Mitochondrial Permeability Transition Pore by the Outer Membrane Does Not Involve the Peripheral Benzodiazepine Receptor (Translocator Protein of 18 kDa (TSPO))

“…On the basis of these studies, we conclude that liver mitochondria lacking TSPO function essentially as do control mitochondria. Whether proposed functions of TSPO in cholesterol and heme transport and in steroidogenesis (1)(2)(3)(4)(5)(6) are compensated by mechanisms that we have not addressed here remains to be established. Indeed, recent similar genetic studies have called into question the precise role of TSPO in steroid hormone biogenesis (7).…”

“…TSPO Is Not Required for Porphyrin-mediated Photodynamic Effects on the PTP-We have previously reported that in isolated mitochondria, the PT can be modulated by photooxidative stress following UV-visible light irradiation of PP IX-like dicarboxylic porphyrins associated with mitochondria, resulting in the production of reactive oxygen species (primarily singlet oxygen, 1 O 2 ) (65). Earlier studies have demonstrated that such photooxidative stress promotes modification of vicinal targets at two critical sites.…”

“…Structural analysis has suggested that it consists of five transmembrane ␣ helices forming a channellike structure that may accommodate the import of lipophilic molecules into mitochondria (1). The C-terminal, cytosolic domain of TSPO contains a high affinity cholesterol recognition sequence, and TSPO has been suggested to play an important role in facilitating the transport of cholesterol from the OMM to the inner mitochondrial membrane (IMM) (2,3).…”

Structure of the mammalian TSPO/PBR protein

“…Mammalian TSPO/PBR is homologues to bacterial TspO proteins, which have a high content of tryptophan residues [39]. Accordingly, several tryptophan residues of mTSPO/PBR are conserved such as Trp 33 Topological analysis has suggested that the flexible Cterminus, the TM3-TM4 loop and the TM1-TM2 loop are located on the extra-mitochondrial side [25].…”

El cáncer bucal y su relación con la proteína translocadora mitocondrial de 18kda

“…En mamíferos, la significancia biológica de la TSPO ha sido estudiada por décadas y ha sido relacionada con múltiples funciones celulares, siendo la regulación del transporte de colesterol a través de las membranas mitocondriales, la función mejor caracterizada (33).…”