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Monomeric structure of the cardioprotective chemokine SDF-1/CXCL12. Protein Sci 2009 Jul;18(7):1359-69

Date

06/25/2009

Pubmed ID

19551879

Pubmed Central ID

PMC2775206

DOI

10.1002/pro.167

Scopus ID

2-s2.0-67650092745   60 Citations

Abstract

The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) directs leukocyte migration, stem cell homing, and cancer metastasis through activation of CXCR4, which is also a coreceptor for T-tropic HIV-1. Recently, SDF-1 was shown to play a protective role after myocardial infarction, and the protein is a candidate for development of new anti-ischemic compounds. SDF-1 is monomeric at nanomolar concentrations but binding partners promote self-association at higher concentrations to form a typical CXC chemokine homodimer. Two NMR structures have been reported for the SDF-1 monomer, but only one matches the conformation observed in a series of dimeric crystal structures. In the other model, the C-terminal helix is tilted at an angle incompatible with SDF-1 dimerization. Using a rat heart explant model for ischemia/reperfusion injury, we found that dimeric SDF-1 exerts no cardioprotective effect, suggesting that the active species is monomeric. To resolve the discrepancy between existing models, we solved the NMR structure of the SDF-1 monomer in different solution conditions. Irrespective of pH and buffer composition, the C-terminal helix remains tilted at an angle with no evidence for the perpendicular arrangement. Furthermore, we find that phospholipid bicelles promote dimerization that necessarily shifts the helix to the perpendicular orientation, yielding dipolar couplings that are incompatible with the NOE distance constraints. We conclude that interactions with the alignment medium biased the previous structure, masking flexibility in the helix position that may be essential for the distinct functional properties of the SDF-1 monomer.

Author List

Veldkamp CT, Ziarek JJ, Su J, Basnet H, Lennertz R, Weiner JJ, Peterson FC, Baker JE, Volkman BF

Authors

John E. Baker PhD Professor in the Surgery department at Medical College of Wisconsin
Francis 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

Animals
Cardiotonic Agents
Chemokine CXCL12
Dimyristoylphosphatidylcholine
Disease Models, Animal
Heart
Histidine
Hydrogen-Ion Concentration
Micelles
Models, Molecular
Myocardial Infarction
Myocardial Reperfusion
Nuclear Magnetic Resonance, Biomolecular
Phosphates
Phospholipid Ethers
Protein Multimerization
Rats
Static Electricity
jenkins-FCD Prod-444 eb4ebd1a08581aba961d3befd3b851a3c3ec6b46