Interactions of ferritin with scavenger receptor class A members

Abstract

Scavenger receptors are a superfamily of membrane-bound receptors that recognize both self and non-self targets. Scavenger receptor class A (SR-A) has five known members (SCARA1 to 5 or SR-A1 to A5), which are type II transmembrane proteins that form homotrimers on cell surface. SR-A members recognize various ligands and are involved in multiple biological pathways. Among them, SCARA5 can function as a ferritin receptor; however, the interaction between SCARA5 and ferritin has not been fully characterized. Here, we determine the crystal structures of the C-terminal scavenger receptor cysteine-rich (SRCR) domain of both human and mouse SCARA5 at 1.7 and 2.5Å resolution, respectively, revealing three Ca2+ binding sites on the surface. Using biochemical assays, we show that the SRCR domain of SCARA5 recognizes ferritin in a Ca2+-dependent manner, and both L- and H-ferritin can be recognized by SCARA5 through the SRCR domain. Furthermore, the potential binding region of SCARA5 on the surface of ferritin is explored by mutagenesis studies. We also examine the interactions of ferritin with other SR-A members and find that SCARA1 (SR-A1, CD204) and MARCO (SR-A2, SCARA2), which are highly expressed on macrophages, also interact with ferritin. By contrast, SCARA3 and SCARA4, the two SR-A members without the SRCR domain, have no detectable binding with ferritin. Overall, these results provide a mechanistic view regarding the interactions between the SR-A members and ferritin that may help to understand the regulation of ferritin homeostasis by scavenger receptors.

Recognition of lipoproteins by scavenger receptor class A members

“…5). Among them, the SRCR domains of SCARA1 and SCARA5 showed higher structural similarities with each other than with the SRCR domain of MARCO, which was consistent with the relatively higher sequence identity between the two molecules (31). The crystal structure of the SRCR domain of human SCARA5 showed three Ca 2+ binding sites referred as site 1 (D419, D420 and E486), site 2 (D458, D459, N481and D420) and site 3 (D423 and D426) (Fig.…”

“…1E). Since the structures of the SRCR domains of human and mouse SCARA5 are highly similar (31), the interactions between mSCARA5 and lipoproteins might need to be further explored.…”

“…Previous reports have shown that the Ca 2+ binding sites were important for the ligand binding of the SRCR domains (31,32). To examine the roles J o u r n a l P r e -p r o o f of Ca 2+ in the recognition of lipoproteins, FACS was applied and the results showed that both the modified LDL and VLDL could bind SCARA1, MARCO and SCARA5 in the presence of Ca 2+ , and the binding was eliminated by the addition of EDTA (Fig.…”

Scavenger Receptor A1 Mediates the Uptake of Carboxylated and Pristine Multi-Walled Carbon Nanotubes Coated with Bovine Serum Albumin

“…Further, SR-A1.1, an alternatively spliced variant of SR-A1 lacking the SRCR domain, still binds oxidized LDL, suggesting that the collagenous domain is the major binding site for this ligand, although this does not rule out that the SRCR domain of SR-A1 may also interact with oxidized LDL or other protein ligands. Indeed, recent work suggests that the SR-A1 SRCR domain binds spectrin [ 45 ] and ferritin [ 46 ]. The SRCR domain is involved in the ligand binding by MARCO, a member of the class A scavenger receptors that shares the highly conserved SRCR domain with SR-A1 [ 47 , 48 , 49 ].…”

Iron: An Essential Element of Cancer Metabolism

“…Noteworthily, ferritin heavy chains can be imported by endocytosis after binding to TfR1 [209]. Scavenger receptor class A member 5 (SCARA5) was also shown to mediate ferritin uptake [210,211].…”