Signal regulatory protein alpha (SIRPalpha)/CD47 interaction and function

Abstract

SIRPalpha is an inhibitory receptor present on myeloid cells that interacts with a widely distributed membrane protein CD47. The activating member SIRPbeta, despite extensive sequence similarity to SIRPalpha in the extracellular region, shows negligible binding to CD47. The SIRPalpha/CD47 interaction is unusual in that it can lead to bidirectional signalling through both SIRPalpha and CD47. This review concentrates on the interactions of SIRPalpha with CD47 where recent data have shed light on the structure of the proteins including determining why the activating SIRPbeta does not bind CD47, evidence of extensive polymorphisms and implication for the evolution and function of this protein and paired receptors in general. The interaction may be modified by endocytosis of the receptors, cleavage by proteolysis and through interactions of surfactant proteins.

Figure 1

Cartoon to show interactions of the extracellular region of the SIRP family. The three IgSF domains of the three SIRPs are shown as ovals (blue) and the single domain of CD47 as an oval (green). SIRPα and SIRPγ can both bind CD47 but SIRPβ does not. SP-A (yellow) denotes lung surfactant protein A that belongs to the collectin family that binds SIRPα giving signals through this protein and potentially blocking its interaction with CD47. A related protein SP-D (not shown) also binds SIRPα [32,33].

Figure 2

Polymorphisms and structure of SIRPα. (A) Alignments of the amino acid sequences of domain 1 of the two commonly studied SIRPα sequences (accession numbers CAA71403 and NP_542970 for sequence 1 and 2 respectively) together with polymorphisms identified in [20]. The positions of polymorphic residues are indicated by giving the residue for each sequence and indicating those that differ from SIRPα (1) by green or for those different from either the two common alleles SIRPα (1) or SIRPα (2) by magenta. Both these proteins bind CD47 with the same affinity [16]. The residues that form contacts with CD47 are highlighted in red and the positions of the beta strands and one helical region are shown above the alignment. (B) The positions of the polymorphic residues are mapped onto the SIRPα domain 1 - CD47 extracellular domain co-crystal structure [17]. The sidechains of the polymorphic residues are indicated with spheres using green and magenta to distinguish the polymorphic residues as in Figure 1A. This figure is from [16] and is reproduced with permission from Cell Press.