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Modeling the Transmembrane Arrangement of the Uncoupling Protein UCP1 and Topological Considerations of the Nucleotide-Binding Site

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Abstract

The uncoupling protein from brown adipose tissue (UCP1) is a mitochondrial proton transporter whose activity is inhibited by purine nucleotides. UCP1, like the other members of the mitochondrial transporter superfamily, is an homodimer and each subunit contains six transmembrane segments. In an attempt to understand the structural elements that are important for nucleotide binding, a model for the transmembrane arrangement of UCP1 has been built by computational methods. Biochemical and sequence analysis considerations are taken as constraints. The main features of the model include the following: (i) the six transmembrane α-helices (TMHs) associate to form an antiparallel helix bundle; (ii) TMHs have an amphiphilic nature and thus the hydrophobic and variable residues face the lipid bilayer; (iii) matrix loops do not penetrate in the core of the bundle; and (iv) the polar core constitutes the translocation pathway. Photoaffinity labeling and mutagenesis studies have identified several UCP1 regions that interact with the nucleotide. We present a model where the nucleotide binds deep inside the bundle core. The purine ring interacts with the matrix loops while the polyphosphate chain is stabilized through interactions with essential Arg residues in the TMH and whose side chains face the core of the helix bundle.

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Authors and Affiliations

  1. Centro de Investigaciones Biológicas, CSIC, Velázquez 144, 28006, Madrid, Spain

    Amalia Ledesma, Mario García de Lacoba & Eduardo Rial

  2. MRC-Dunn Human Nutrition Unit, Welcome/MRC Building, Cambridge, United Kingdom

    Ignacio Arechaga

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  1. Amalia Ledesma
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  2. Mario García de Lacoba
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  3. Ignacio Arechaga
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  4. Eduardo Rial
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Ledesma, A., Lacoba, M.G.d., Arechaga, I. et al. Modeling the Transmembrane Arrangement of the Uncoupling Protein UCP1 and Topological Considerations of the Nucleotide-Binding Site. J Bioenerg Biomembr 34, 473–486 (2002). https://doi.org/10.1023/A:1022522310279

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