Document Detail


Heparin oligosaccharides inhibit chemokine (CXC motif) ligand 12 (CXCL12) cardioprotection by binding orthogonal to the dimerization interface, promoting oligomerization, and competing with the chemokine (CXC motif) receptor 4 (CXCR4) N terminus.
MedLine Citation:
PMID:  23148226     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The ability to interact with cell surface glycosaminoglycans (GAGs) is essential to the cell migration properties of chemokines, but association with soluble GAGs induces the oligomerization of most chemokines including CXCL12. Monomeric CXCL12, but not dimeric CXCL12, is cardioprotective in a number of experimental models of cardiac ischemia. We found that co-administration of heparin, a common treatment for myocardial infarction, abrogated the protective effect of CXCL12 in an ex vivo rat heart model for myocardial infarction. The interaction between CXCL12 and heparin oligosaccharides has previously been analyzed through mutagenesis, in vitro binding assays, and molecular modeling. However, complications from heparin-induced CXCL12 oligomerization and studies using very short oligosaccharides have led to inconsistent conclusions as to the residues involved, the orientation of the binding site, and whether it overlaps with the CXCR4 N-terminal site. We used a constitutively dimeric variant to simplify the NMR analysis of CXCL12-binding heparin oligosaccharides of varying length. Biophysical and mutagenic analyses reveal a CXCL12/heparin interaction surface that lies perpendicular to the dimer interface, does not involve the chemokine N terminus, and partially overlaps with the CXCR4-binding site. We further demonstrate that heparin-mediated enzymatic protection results from the promotion of dimerization rather than direct heparin binding to the CXCL12 N terminus. These results clarify the structural basis for GAG recognition by CXCL12 and lend insight into the development of CXCL12-based therapeutics.
Authors:
Joshua J Ziarek; Christopher T Veldkamp; Fuming Zhang; Nathan J Murray; Gabriella A Kartz; Xinle Liang; Jidong Su; John E Baker; Robert J Linhardt; Brian F Volkman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-12
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  288     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-07     Completed Date:  2013-02-28     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  737-46     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Binding Sites
Biophysics / methods
Cardiotonic Agents / chemistry
Chemokine CXCL12 / metabolism*
Chemokines / metabolism
Dimerization
Glycosaminoglycans / chemistry
Heparin / chemistry
Humans
Inhibitory Concentration 50
Kinetics
Magnetic Resonance Spectroscopy / methods
Models, Molecular
Molecular Conformation
Myocardial Infarction / metabolism
Oligosaccharides / chemistry*
Perfusion
Protein Structure, Tertiary
Rats
Receptors, CXCR4 / metabolism*
Grant Support
ID/Acronym/Agency:
1-R15CA159202-01/CA/NCI NIH HHS; AI058072/AI/NIAID NIH HHS; AI063325/AI/NIAID NIH HHS; AI080363/AI/NIAID NIH HHS; GM097381/GM/NIGMS NIH HHS; GM38060/GM/NIGMS NIH HHS; HL54075/HL/NHLBI NIH HHS; HL62244/HL/NHLBI NIH HHS; R01 AI058072/AI/NIAID NIH HHS; R01 GM097381/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/CXCL12 protein, human; 0/CXCR4 protein, human; 0/Cardiotonic Agents; 0/Chemokine CXCL12; 0/Chemokines; 0/Glycosaminoglycans; 0/Oligosaccharides; 0/Receptors, CXCR4; 9005-49-6/Heparin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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