From the Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
J Biol Chem. 2014 Apr 4;289(14):10024-8. doi: 10.1074/jbc.M114.550558. Epub 2014 Feb 18.
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.
CD47 是一种广泛分布的膜蛋白，与信号调节蛋白 α（SIRPα）相互作用，SIRPα 是髓系细胞上的一种抑制性受体，能发出“不要吃我”的信号。该相互作用的人为操控在癌症的免疫疗法和异种移植中具有重要意义。与 CD47 的单一免疫球蛋白样结构域相反，SIRPα 的氨基末端配体结合域高度多态性。人们对于这些多态性是否会影响配体结合存在争议，但这是该相互作用以及其他配对受体被视为治疗靶点的一个重要问题。我们通过 X 射线晶体学表明，一个人类 SIRPα 等位基因有 13 个氨基酸残基的差异，其具有非常相似的结合位点，并且几种不同的等位基因都以预期的相似亲和力结合 CD47，因为这些残基主要位于表面且远离结合位点。据报道，来自 CD47 结合位点的肽可以模拟 CD47 与 SIRPα 的相互作用，但我们没有发现任何结合。我们讨论了确定弱相互作用亲和力的可能陷阱，并推测 SIRPα 多态性如何被病原体选择，以及这在其他配对受体（如 KIR）中是否也是如此。
