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Published on: December 3, 2020
Polymorphisms in the human inhibitory signal-regulatory protein α do not affect binding to its ligand CD47
Deborah Hatherley1, Susan M Lea, Steven Johnson
1From the Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
Abstract:
CD47 is a widely distributed membrane protein that interacts with signal-regulatory protein α (SIRPα), an inhibitory receptor on myeloid cells that gives a "don't-eat-me" signal. Manipulation of the interaction is of considerable interest in the immunotherapy of cancer and in xenotransplantation. The amino-terminal ligand binding domain of SIRPα is highly polymorphic in contrast to the single Ig-like domain of CD47. There is confusion as to whether the polymorphisms will affect ligand binding, but this is an important point for this interaction and other paired receptors being considered as targets for therapy. We show by x-ray crystallography that one human SIRPα allele differing in 13 amino acid residues has a very similar binding site and that several different alleles all bind CD47 with similar affinity as expected because the residues are mostly surface-exposed and distant from the binding site. A peptide from the binding site of CD47 has been reported to mimic the CD47 interaction with SIRPα, but we could find no binding. We discuss the possible pitfalls in determining the affinity of weak interactions and also speculate on how SIRPα polymorphisms may have been selected by pathogens and how this may also be true in other paired receptors such as the KIRs.
Insights
Polymorphisms in signal-regulatory protein α (SIRPα) do not affect its binding affinity to CD47, a key target in cancer immunotherapy and xenotransplantation. This finding clarifies interactions crucial for therapeutic development.
Area of Science:
- Immunology
- Structural Biology
- Biochemistry
Background:
- CD47 is a cell surface protein interacting with signal-regulatory protein α (SIRPα) on myeloid cells, mediating a "don't-eat-me" signal.
- This CD47-SIRPα interaction is a significant target for cancer immunotherapy and xenotransplantation research.
- SIRPα exhibits polymorphisms in its ligand-binding domain, raising questions about their impact on CD47 binding and therapeutic potential.
Purpose of the Study:
- To investigate the impact of SIRPα polymorphisms on CD47 binding affinity.
- To clarify the structural basis of the CD47-SIRPα interaction.
- To evaluate the efficacy of CD47-derived peptides as mimics of the interaction.
Main Methods:
- X-ray crystallography was employed to determine the structure of SIRPα alleles.
- Binding affinity assays were performed to quantify the interaction between different SIRPα alleles and CD47.
- Peptide binding assays were conducted to assess mimicry of the CD47-SIRPα interaction.
Main Results:
- Human SIRPα alleles with significant amino acid differences (13 residues) displayed highly similar binding sites for CD47.
- Multiple SIRPα alleles demonstrated comparable binding affinities for CD47, as the polymorphic residues are surface-exposed and distant from the binding interface.
- A reported CD47-derived peptide failed to show binding to SIRPα, indicating it does not effectively mimic the natural interaction.
Conclusions:
- SIRPα polymorphisms do not significantly alter CD47 binding affinity, simplifying therapeutic targeting strategies.
- The structural basis of the CD47-SIRPα interaction is conserved across different alleles, supporting its role in immune regulation.
- Careful consideration of experimental methods is crucial for accurately assessing weak molecular interactions, particularly in therapeutic contexts.
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