The mitochondrial uncoupling protein UCP1: a gated pore.

Area of Science:

• Mitochondrial physiology
• Membrane transport proteins
• Bioenergetics

Background:

• Uncoupling protein 1 (UCP1) belongs to a superfamily of mitochondrial metabolite transporters.
• These transporters exhibit dual functionality, acting as carriers in vivo and channels under specific conditions.
• This suggests a structure with distinct functional and structural domains, potentially a gated pore.

Purpose of the Study:

• To propose a structural model for UCP1's nucleotide binding site.
• To elucidate the mechanism of UCP1 regulation by nucleotides and fatty acids.
• To understand the role of specific residues and domains in UCP1 transport and gating.

Main Methods:

• Photoaffinity labeling studies to identify binding sites.
• Site-directed mutagenesis to probe residue function.
• Kinetic analysis based on the 'single binding center gated pore' model.

Main Results:

• A structural model places the nucleotide binding site deep within the protein, accessible via a cytosolic gate.
• Matrix loops form a hydrophobic pocket for the purine moiety, while arginine residues interact with phosphate groups.
• His214 and Glu190 on the cytosolic side are proposed to regulate nucleotide access through pH-dependent protonation.

Conclusions:

• UCP1's dual carrier-channel behavior is explained by a gated pore model.
• The proposed model details the structural basis for nucleotide binding and regulation.
• Understanding UCP1 structure is crucial for its physiological roles in regulating proton conductance and energy metabolism.