Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 105 (13): 5057-5062

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

Interconversion between two unrelated protein folds in the lymphotactin native state

Robbyn L. Tuinstra*, Francis C. Peterson*, Snjezana Kutlesa{dagger}, E. Sonay Elgin{ddagger}, Michael A. Kron{dagger},§, and Brian F. Volkman*,¶

Departments of *Biochemistry and §Medicine and {dagger}Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, WI 53226; and {ddagger}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 publication 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.

Key Words: chemokine • conformational change • NMR spectroscopy

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.

To whom correspondence should be addressed. E-mail: bvolkman{at}mcw.edu

© 2008 by The National Academy of Sciences of the USA

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Evolutionary bridges to new protein folds: design of C-terminal Cro protein chameleon sequences.
W. J. Anderson, L. O. Van Dorn, W. M. Ingram, and M. H. J. Cordes (2011)
Protein Eng. Des. Sel. 24, 765-771
   Abstract »    Full Text »    PDF »
Issues in bioinformatics benchmarking: the case study of multiple sequence alignment.
M. R. Aniba, O. Poch, and J. D. Thompson (2010)
Nucleic Acids Res. 38, 7353-7363
   Abstract »    Full Text »    PDF »
Metamorphic proteins mediate evolutionary transitions of structure.
I. Yadid, N. Kirshenbaum, M. Sharon, O. Dym, and D. S. Tawfik (2010)
PNAS 107, 7287-7292
   Abstract »    Full Text »    PDF »
One sequence plus one mutation equals two folds.
D. Shortle (2009)
PNAS 106, 21011-21012
   Full Text »    PDF »
A minimal sequence code for switching protein structure and function.
P. A. Alexander, Y. He, Y. Chen, J. Orban, and P. N. Bryan (2009)
PNAS 106, 21149-21154
   Abstract »    Full Text »    PDF »
Direct single-molecule observation of a protein living in two opposed native structures.
Y. Gambin, A. Schug, E. A. Lemke, J. J. Lavinder, A. C. M. Ferreon, T. J. Magliery, J. N. Onuchic, and A. A. Deniz (2009)
PNAS 106, 10153-10158
   Abstract »    Full Text »    PDF »
Protein Dynamism and Evolvability.
N. Tokuriki and D. S. Tawfik (2009)
Science 324, 203-207
   Abstract »    Full Text »    PDF »
ARNT PAS-B has a fragile native state structure with an alternative {beta}-sheet register nearby in sequence space.
M. R. Evans, P. B. Card, and K. H. Gardner (2009)
PNAS 106, 2617-2622
   Abstract »    Full Text »    PDF »
BIOCHEMISTRY: Metamorphic Proteins.
A. G. Murzin (2008)
Science 320, 1725-1726
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882