Receptor recognition or nonrecognition has been shown for these molecules, either through direct binding studies or the inhibition of modified lipoprotein endocytosis. and affinities may depend on the regulated folding of the receptor, which would influence the extent of contact between domains. The construction of suitable mutants that either promote or prevent flexible articulation of the receptor should permit testing of this hypothesis. It would be of interest to examine whether similar binding properties are observed with ligands other than AcLDL, or if configuration has a greater or lesser effect on their recognition. Interestingly, a naturally occurring mutation of SR-A in the C57/BL6 mouse strain has recently been described, which has been identified as amino-acid changes in the α-helical coiled-coil domain that affect receptor immunoreactivity, but apparently not function (9, 10). Detailed kinetic studies of this or other sequence variants may reveal important clues to the relationship between ligand binding and the receptor’s conformational state. SR-A shares with SR-B1 (see Krieger, this Perspective series, ref. 4) an unusual binding property referred to as nonreciprocal cross-competition of ligands (1). This term is used to describe a situation in which ligand A can completely compete for the binding of ligand B, but the latter cannot effectively displace the former. For example, although oxLDL inhibits the binding of acLDL by SR-A totally, acLDL can only block that of oxLDL partially. The structural basis of this pattern of ligand binding is unclear, although it has been interpreted as reflecting the existence of two discrete but overlapping ligand binding sites on the receptor. Nonreciprocal interactions have been observed so far only in experiments with cultured cells, but the prospect that they occur in vivo raises exciting possibilities. In particular, such a situation would favor the hierarchical and sequential interactions of the receptor with different ligands and thus might account for some of the biological complexity of SR function. For instance, under some circumstances, SR-A might colocalize with a known ligand but fail to bind it because another ligand is bound preferentially, even though the latter interaction may be of similar or lower affinity. In order to define the receptor-ligand events fully, it will be necessary to identify all the types of SRs and characterize all the ligands that are present in any given biological context. With the cloning of the gene for the bovine SR-A, two transcripts were identified encoding different forms of the receptor (1). Identical isoforms have been shown in the subsequent cloning of the murine, human, and rabbit homologues (11). Type I SR-A is distinguished by the presence of an additional C-terminal region, the SR cysteine-rich (SRCR) domain. Not only has this domain been conserved in the SR-As of other mammals, it has been found in a number of proteins across different phyla (12). Because it has not so far been shown to influence the binding of modified lipoprotein, the presence of SRCR-like motifs is not predictive of SR activity. However, its conservation implies an unidentified function. The potential identification of molecules that bind specifically to the SRCR domain and not the collagenous region could reveal significant biological interactions, but to date, with a few relatively minor exceptions, the binding properties of type I and type II SR-A are currently considered identical. The recent generation of a mouse lacking type I but retaining type II expression may clarify the role of the SRCR (M. de Winther and M. Hofker, personal communication). Although other SRs have been identified in invertebrates, no obvious homologues of SR-A …