Interconversion between two unrelated protein folds in the lymphotactin native state

doi:10.1073/pnas.0709518105

Interconversion between two unrelated protein folds in the lymphotactin native state

Departments of *Biochemistry and
^§Medicine and
^†Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI 53226; and
^‡Department of Chemistry, Kimya Bölümü Mugla Üniversitesi, Mugla 48000, Turkey

Edited by S. Walter Englander, University of Pennsylvania School of Medicine, Philadelphia, PA, and approved February 1, 2008 (received for review October 6, 2007)

Abstract

Proteins often have multiple functional states, which might not always be accommodated by a single fold. Lymphotactin (Ltn) adopts two distinct structures in equilibrium, one corresponding to the canonical chemokine fold consisting of a monomeric three-stranded β-sheet and carboxyl-terminal helix. The second Ltn structure solved by NMR reveals a dimeric all-β-sheet arrangement with no similarity to other known proteins. In physiological solution conditions, both structures are significantly populated and interconvert rapidly. Interconversion replaces long-range interactions that stabilize the chemokine fold with an entirely new set of tertiary and quaternary contacts. The chemokine-like Ltn conformation is a functional XCR1 agonist, but fails to bind heparin. In contrast, the alternative structure binds glycosaminoglycans with high affinity but fails to activate XCR1. Because each structural species displays only one of the two functional properties essential for activity in vivo, the conformational equilibrium is likely to be essential for the biological activity of lymphotactin. These results demonstrate that the functional repertoire and regulation of a single naturally occurring amino acid sequence can be expanded by access to a set of highly dissimilar native-state structures.

Footnotes

^¶To whom correspondence should be addressed. E-mail: bvolkman{at}mcw.edu
Author contributions: F.C.P., M.A.K., and B.F.V. designed research; R.L.T., F.C.P., S.K., E.S.E., and B.F.V. performed research; R.L.T. and F.C.P. contributed new reagents/analytic tools; R.L.T., F.C.P., S.K., E.S.E., and B.F.V. analyzed data; and R.L.T., F.C.P., and B.F.V. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: Atomic coordinates and chemical shift assignments for Ltn40 have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2JP1) and the BioMagResBank, www.bmrb.wisc.edu (accession no. 15215).
This article contains supporting information online at www.pnas.org/cgi/content/full/0709518105/DCSupplemental.