Structures of secreted forms of the human type I and II class A macrophage scavenger receptors were studied using biochemical and biophysical methods. Proteolytic analysis was used to determine the intramolecular disulfide bonds in the type I-specific scavenger receptor cysteine-rich (SRCR) domain: Cys 2 -Cys 7 , Cys 3 -Cys 8 , and Cys 5 -Cys 6 . This pattern is likely to be shared by the highly homologous domains in the many other members of the SRCR domain superfamily. Electron microscopy using rotary shadowing and negative staining showed that the type I and II receptors are extended molecules whose contour lengths are ϳ440 Å. They comprised two adjacent fibrous segments, an ␣-helical coiled-coil (ϳ230 Å, including a contribution from the N-terminal spacer domain) and a collagenous triple helix (ϳ210 Å). The type I molecules also contained a C-terminal globular structure (ϳ58 ؋ 76 Å) composed of three SRCR domains. The fibrous domains were joined by an extremely flexible hinge. The angle between these domains varied from 0 to 180°and depended on the conditions of sample preparation. Unexpectedly, at physiologic pH, the prevalent angle seen using rotary shadowing was 0°, resulting in a structure that is significantly more compact than previously suggested. The apparent juxtaposition of the fibrous domains at neutral pH provides a framework for future structure-function studies of these unusual multiligand receptors.The type I and II class A macrophage scavenger receptors (SR-AI and SR-AII) 1 are trimeric integral membrane glycoproteins that exhibit unusual ligand binding properties (Krieger and Herz, 1994). They bind a diverse array of macromolecules or macromolecular complexes, whose only common property is that they are polyanionic. These ligands include modified lipoproteins (acetylated or oxidized low density lipoprotein), bacterial surface lipids (endotoxin and lipoteichoic acid), certain polynucleotides (poly(G) and poly(I), but not poly(C)), and some sulfated polysaccharides (fucoidan and dextran sulfate, but not heparin or chondroitin sulfate). A number of studies have suggested that these receptors may play a role in a wide variety of macrophage-associated physiologic and pathophysiologic processes (Krieger and Herz, 1994).SR-AI and SR-AII are the alternatively spliced products of a single gene Emi et al., 1993). Based on their amino acid sequences deduced from cDNA clones from four species Rohrer et al., 1990;Matsumoto et al., 1990;Freeman et al., 1990;Ashkenas et al., 1993;Bickel and Freeman, 1992), SR-AI and SR-AII were predicted to contain six distinct structural domains Rohrer et al., 1990;Ashkenas et al., 1993): I, an amino-terminal cytoplasmic domain; II, a single transmembrane domain; III, a spacer domain; IV, an ␣-helical coiled-coil domain; V, a collagenous domain; and VI, an isotype-specific C-terminal domain of variable length. Domains I-V are identical in SR-AI and SR-AII. In SR-AII, domain VI consists of a poorly conserved, short sequence (6 -17 amino acids) with no remarkable features. ...