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Published on: September 29, 2019
Monomeric structure of the cardioprotective chemokine SDF-1/CXCL12
Christopher T Veldkamp1, Joshua J Ziarek, Jidong Su
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Insights
Stromal cell-derived factor-1 (SDF-1/CXCL12) is crucial for cell migration. This study reveals that the monomeric form, not the dimer, is cardioprotective after ischemia, challenging previous structural models.
Area of Science:
- Biochemistry
- Structural Biology
- Cardiovascular Research
Background:
- Stromal cell-derived factor-1 (SDF-1/CXCL12) is a chemokine involved in cell migration and homing.
- SDF-1 activates CXCR4, a coreceptor for HIV-1, and shows potential as an anti-ischemic compound.
- SDF-1 exists as a monomer at low concentrations and can form dimers with binding partners.
Purpose of the Study:
- To resolve discrepancies in reported SDF-1 monomer structures.
- To investigate the structural basis for SDF-1's cardioprotective role after myocardial infarction.
- To determine whether monomeric or dimeric SDF-1 is the active species in cardioprotection.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy to determine SDF-1 monomer structure under various conditions.
- Rat heart explant model to assess cardioprotective effects of dimeric vs. monomeric SDF-1 in ischemia/reperfusion injury.
- Analysis of dipolar couplings and NOE distance constraints to evaluate structural models.
Main Results:
- The C-terminal helix of SDF-1 monomer consistently adopts a tilted conformation, irrespective of pH or buffer.
- Phospholipid bicelles induce dimerization, shifting the helix to a perpendicular orientation incompatible with NMR constraints.
- Dimeric SDF-1 showed no cardioprotective effect in a rat heart explant model, while the monomeric form is suggested to be active.
Conclusions:
- Previous SDF-1 structures may have been biased by the alignment medium used (e.g., bicelles).
- The flexibility of the C-terminal helix is crucial for SDF-1's distinct functional properties, including cardioprotection.
- The monomeric form of SDF-1 is likely the biologically active species mediating cardioprotection after ischemia/reperfusion injury.
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.
