The orphan receptor C5L2/pgpr77, which shares 35% amino identity with CD88, is a promiscuous complement fragment-binding protein. C5L2 binds C5a with high affinity but has a 10-fold higher affinity for C5adR than CD88. C5L2 also has an affinity for C4a and C3a, and their metabolites C4a des-Arg, and C3a des-Arg. C3a binds at a site distinct from the C5a binding site. C5L2 transfected into cells does not support degranulation or increases in intracellular [Ca2+] and is not rapidly internalized in response to ligand binding. However, ligation of C5L2 by anaphylatoxin potentiates the degranulation response to cross-linkage of the high affinity IgE receptor suggesting that C5L2 is an anaphylatoxin-binding protein with unique ligand binding and signalling properties. C5L2 is proposed to mediate the acylation-stimulating properties of C3a des-Arg/ASP.C5L2 is expressed in granulocytes, in mature dendritic cells, adipose tissue and fibroblasts.