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Characterization of the unfolded state of bovine -lactalbumin and comparison with unfolded states of homologous proteins

¹ Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, D-60439 Frankfurt, Germany
² Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
³ Department of Biochemistry and Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom

(RECEIVED November 11, 2005; FINAL REVISION February 21, 2006; ACCEPTED February 25, 2006)

The unfolded states of three homologous proteins with a very similar fold have been investigated by heteronuclear NMR spectroscopy. Secondary structure propensities as derived from interpretation of chemical shifts and motional restrictions as evidenced by heteronuclear ¹⁵N relaxation rates have been analyzed in the reduced unfolded states of hen lysozyme and the calcium-binding proteins bovine -lactalbumin and human -lactalbumin. For all three proteins, significant deviations from random-coil predictions can be identified; in addition, the unfolded states also differ from each other, despite the fact that they possess very similar structures in their native states. Deviations from random-coil motional properties are observed in the - and the -domain in bovine -lactalbumin and lysozyme, while only regions within the -domain deviate in human -lactalbumin. The motional restrictions and residual secondary structure are determined both by the amino acid sequence of the protein and by residual long-range interactions. Even a conservative single point mutation from I to L in a highly conserved region between the two -lactalbumins results in considerable differences in the motional properties. Given the differences in oxidative folding between hen lysozyme and -lactalbumin, the results obtained on the unfolded states suggest that residual long-range interactions, i.e., those between the - and the -domain of lysozyme, may act as nucleation sites for protein folding, while this property of residual structure is replaced by the calcium-binding site between the domains in -lactalbumin.

Keywords: NMR spectroscopy; unfolded proteins; protein folding; -lactalbumin; lysozyme

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