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|Title: ||Sulfopeptide probes of the CXCR4/CXCL12 interface reveal oligomer-specific contacts and chemokine allostery|
|Authors: ||Ziarek, Joshua J.|
Getschman, Anthony E.
Butler, Stephen J.
Handel, Tracy M.
Payne, Richard J.
Volkman, Brian F.
|Issue Date: ||2013|
|Publisher: ||© American Chemical Society|
|Citation: ||ZIAREK, J.J. ... et al, 2013. Sulfopeptide probes of the CXCR4/CXCL12 interface reveal oligomer-specific contacts and chemokine allostery. ACS Chemical Biology, 8 (9), pp. 1955 - 1963.|
|Abstract: ||Tyrosine sulfation is a post-translational modification that enhances protein–protein interactions and may identify druggable sites in the extracellular space. The G protein-coupled receptor CXCR4 is a prototypical example with three potential sulfation sites at positions 7, 12, and 21. Each receptor sulfotyrosine participates in specific contacts with its chemokine ligand in the structure of a soluble, dimeric CXCL12:CXCR4(1–38) complex, but their relative importance for CXCR4 binding and activation by the monomeric chemokine remains undefined. NMR titrations with short sulfopeptides showed that the tyrosine motifs of CXCR4 varied widely in their contributions to CXCL12 binding affinity and site specificity. Whereas the Tyr21 sulfopeptide bound the same site as in previously solved structures, the Tyr7 and Tyr12 sulfopeptides interacted nonspecifically. Surprisingly, the unsulfated Tyr7 peptide occupied a hydrophobic site on the CXCL12 monomer that is inaccessible in the CXCL12 dimer. Functional analysis of CXCR4 mutants validated the relative importance of individual CXCR4 sulfotyrosine modifications (Tyr21 > Tyr12 > Tyr7) for CXCL12 binding and receptor activation. Biophysical measurements also revealed a cooperative relationship between sulfopeptide binding at the Tyr21 site and CXCL12 dimerization, the first example of allosteric behavior in a chemokine. Future ligands that occupy the sTyr21 recognition site may act as both competitive inhibitors of receptor binding and allosteric modulators of chemokine function. Together, our data suggests that sulfation does not ubiquitously enhance complex affinity and that distinct patterns of tyrosine sulfation could encode oligomer selectivity, implying another layer of regulation for chemokine signaling.|
|Description: ||This article is closed access.|
|Sponsor: ||This work was
supported by a Postdoctoral Fellowship from the Medical
College of Wisconsin Cancer Center (J.J.Z.); National
Institutes of Health grants R01AI058072, R01GM097381,
and R56AI063325 (BFV) and U01GM094612 and
R01GM081763 (T.M.H.); Cellular and Molecular Pharmacology
Training Grant T32GM007752 (B.S.); and an Individual
Ruth L. Kirschstein National Research Service Award
Postdoctoral Fellowship F32GM103005 (J.J.Z.). This work
was also supported by an Australian Research Council
Discovery Project Grant (R.J.P.) and an Australian Postgraduate
|Publisher Link: ||http://dx.doi.org/10.1021/cb400274z|
|Appears in Collections:||Closed Access (Chemistry)|
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