Uncoupling Proteins of the Central Nervous System:Comparative Biophysical Studies

Abstract

Molecular properties and physiological roles of the uncoupling proteins (UCPs) in the Central Nervous System (CNS) is an open question. In general, UCPs reduce the proton motive force across the mitochondrial inner membrane and uncouple the electron transfer process from ATP synthesis. Three of the five identified human UCPs (UCPs 2, 4 and 5) have been discovered in the CNS tissues. It has been widely suggested that the neuronal UCPs share common conformational and physiological properties with the prototypic UCP1, and have essential roles in the function and protection of the CNS. In addition to its uncoupling property, UCP1 has a distinct thermogenic role in brown adipose tissues. Important roles of neuronal UCPs may include thermal enhancement of synaptic neurotransmission and plasticity, and reduction of reactive oxygen species as one of the causes of neurodegenerative diseases. Despite extensive biological studies on UCPs, the structural properties and molecular details of the mechanisms of their functions are not clearly understood. In the past decade, our research group has been involved in comparative studies of the neuronal uncoupling proteins. Using CD and fluorescence spectroscopies and other biophysical techniques, we have shown that, despite their low sequence identity with each other and with UCP1, neuronal UCPs share common (dominantly helical) conformational features. Detailed studies in our laboratory also revealed the existence of common ion transport (proton and chloride) features in neuronal UCPs. To further clarify the molecular details of the physiological function of neuronal UCPs, we have proposed a simple molecular model for the coexistence of monomeric, dimeric and tetrameric functional forms of UCPs. These comparative studies emphasize on the subtle structural and functional differences between neuronal UCPs and their complex self-association that can be crucial in differentiating their physiological roles.