Interconversion between two unrelated protein folds in the lymphotactin native state. Proc Natl Acad Sci U S A 2008 Apr 01;105(13):5057-62
Date
03/28/2008Pubmed ID
18364395Pubmed Central ID
PMC2278211DOI
10.1073/pnas.0709518105Scopus ID
2-s2.0-42449084477 (requires institutional sign-in at Scopus site) 229 CitationsAbstract
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 beta-sheet and carboxyl-terminal helix. The second Ltn structure solved by NMR reveals a dimeric all-beta-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.
Author List
Tuinstra RL, Peterson FC, Kutlesa S, Elgin ES, Kron MA, Volkman BFAuthors
Michael Kron MD Director, Professor in the Medicine department at Medical College of WisconsinFrancis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
DimerizationHumans
Lymphokines
Models, Molecular
Nuclear Magnetic Resonance, Biomolecular
Protein Denaturation
Protein Folding
Protein Structure, Quaternary
Protein Structure, Tertiary
Sialoglycoproteins
