| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
(RECEIVED November 4, 2004; FINAL REVISION January 4, 2005; ACCEPTED January 4, 2005)
Chemokines, like stromal cell-derived factor-1 (SDF1/CXCL12), are small secreted proteins that signal cells to migrate. Because SDF1 and its receptor CXCR4 play important roles in embryonic development, cancer metastasis, and HIV/AIDS, this chemokine signaling system is the subject of intense study. However, it is not known whether the monomeric or dimeric structure of SDF1 is responsible for signaling in vivo. Previous structural studies portrayed the SDF1 structure as either strictly monomeric in solution or dimeric when crystallized. Here, we report two-dimensional NMR, pulsed-field gradient diffusion and fluorescence polarization measurements at various SDF1 concentrations, solution conditions, and pH. These results demonstrate that SDF1 can form a dimeric structure in solution, but only at nonacidic pH when stabilizing counterions are present. Thus, while the previous NMR structural studies were performed under acidic conditions that strongly promote the monomeric state, crystallographic studies used nonacidic buffer conditions that included divalent anions shown here to promote dimerization. This pH-sensitive aggregation behavior is explained by a dense cluster of positively charged residues at the SDF1 dimer interface that includes a histidine side chain at its center. A heparin disaccharide shifts the SDF1 monomer–dimer equilibrium in the same manner as other stabilizing anions, suggesting that glycosaminoglycan binding may be coupled to SDF1 dimerization in vivo.
Keywords: chemokines; heparin; NMR; fluorescence polarization; monomer–dimer equilibrium
Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041219505.
Reprint requests to: Brian F. Volkman, Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; e-mail: bvolkman{at}mcw.edu; fax: (414) 456-6510.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Fermas, F. Gonnet, A. Sutton, N. Charnaux, B. Mulloy, Y. Du, F. Baleux, and R. Daniel Sulfated oligosaccharides (heparin and fucoidan) binding and dimerization of stromal cell-derived factor-1 (SDF-1/CXCL 12) are coupled as evidenced by affinity CE-MS analysis Glycobiology, December 1, 2008; 18(12): 1054 - 1064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. T. Veldkamp, C. Seibert, F. C. Peterson, N. B. De la Cruz, J. C. Haugner III, H. Basnet, T. P. Sakmar, and B. F. Volkman Structural Basis of CXCR4 Sulfotyrosine Recognition by the Chemokine SDF-1/CXCL12 Sci. Signal., September 16, 2008; 1(37): ra4 - ra4. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hachet-Haas, K. Balabanian, F. Rohmer, F. Pons, C. Franchet, S. Lecat, K. Y. C. Chow, R. Dagher, P. Gizzi, B. Didier, et al. Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12 J. Biol. Chem., August 22, 2008; 283(34): 23189 - 23199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. I. Chan, H. N. Hunter, B. F. Tack, and H. J. Vogel Human Macrophage Inflammatory Protein 3{alpha}: Protein and Peptide Nuclear Magnetic Resonance Solution Structures, Dimerization, Dynamics, and Anti-Infective Properties Antimicrob. Agents Chemother., March 1, 2008; 52(3): 883 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jin, X. Shen, B. R. Baggett, X. Kong, and P. J. LiWang The Human CC Chemokine MIP-1beta Dimer Is Not Competent to Bind to the CCR5 Receptor J. Biol. Chem., September 21, 2007; 282(38): 27976 - 27983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Murphy, Y. Cho, A. Sachpatzidis, C. Fan, M. E. Hodsdon, and E. Lolis Structural and Functional Basis of CXCL12 (Stromal Cell-derived Factor-1{alpha}) Binding to Heparin J. Biol. Chem., March 30, 2007; 282(13): 10018 - 10027. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Guyon and J.-L. Nahon Multiple actions of the chemokine stromal cell-derived factor-1{alpha} on neuronal activity J. Mol. Endocrinol., March 1, 2007; 38(3): 365 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. K. Baryshnikova and B. D. Sykes Backbone dynamics of SDF-1{alpha} determined by NMR: Interpretation in the presence of monomer-dimer equilibrium. Protein Sci., November 1, 2006; 15(11): 2568 - 2578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Paredes, G. Li, O. Berger, S. C. Baraban, and S. J. Pleasure Stromal-Derived Factor-1 (CXCL12) Regulates Laminar Position of Cajal-Retzius Cells in Normal and Dysplastic Brains. J. Neurosci., September 13, 2006; 26(37): 9404 - 9412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Altundag, O. Altundag, M. A. Atik, C. Boruban, M. B. Altundag, and S. Turen Recent findings for anti-metastatic potential of heparin. Clinical and Applied Thrombosis/Hemostasis, July 1, 2006; 12(3): 376 - 377. [PDF]
|
|
|
|
 |
|
 K. Altundag, O. Altundag, and M. A. Atik Heparin and CXCL12 Dimerization J. Clin. Oncol., October 1, 2005; 23(28): 7248 - 7248. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
