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A more recent version of this article appeared on May 10, 2002
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Papers In Press, published online ahead of print March 11, 2002
J. Biol. Chem, 10.1074/jbc.M200402200
Submitted on January 14, 2002
Revised on March 6, 2002
Accepted on March 11, 2002

Structural rearrangement of human lymphotactin, a C chemokine, under physiological solution conditions

E. Sonay Kuloglu, Darrell R. McCaslin, John L. Markley, and Brian F. Volkman

Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226

Corresponding Author: bvolkman{at}mcw.edu

NMR spectra of human lymphotactin (hLtn), obtained under various solution conditions, revealed that the protein undergoes a major conformational rearrangement dependent on temperature and salt concentration. At high salt (200 mM NaCl) and low temperature (10 °C) hLtn adopts a chemokine-like fold, which consists of a three-stranded anti-parallel beta -sheet and a C terminal alpha -helix [Kulo?lu, E. S., McCaslin, D. R., Kitabwalla, M., Pauza, C. D., Markley, J. L., and Volkman, B. F. (2001) Biochemistry 40, 12486-12496]. We have used NMR spectroscopy, sedimentation equilibrium and intrinsic fluorescence to monitor the reversible conformational change undergone by hLtn as a function of temperature and ionic strength and have used two-, three- and four-dimensional NMR spectroscopy of isotopically enriched protein samples to determine structural properties of the conformational state stabilized at 45 °C and 0 mM NaCl. Patterns of NOEs and 1rHalpha r and 13rC chemical shifts show that hLtn rearranges under these conditions to form a four-stranded, anti-parallel beta -sheet with a pattern of hydrogen bonding that is completely different from that of the chemokine fold stabilized at 10 °C and 200 mM NaCl. The C-terminal alpha -helix observed at 10 °C and 200 mM NaCl, which is conserved in other chemokines, is absent at 45 °C and no salt, and the last 38 residues of the protein are completely disordered, as indicated by heteronuclear 15rN-1rH NOEs. Temperature dependence of the tryptophan fluorescence of hLtn in low and high salt confirmed that the chemokine conformation is stabilized by increased ionic strength. Sedimentation equilibrium analytical ultracentrifugation showed that hLtn at 40 °C in the presence of 100 mM NaCl exists mainly as a dimer. Under near-physiological conditions of temperature, pH, and ionic strength, both the chemokine-like and non-chemokine-like conformations of hLtn are significantly populated. The functional relevance of this structural interconversion remains to be elucidated.




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