Abstract
Scavenger receptors are a superfamily of membrane-bound receptors that recognize both self and nonself 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 the 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 2.5 Å 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.
Highlights
Scavenger receptors (SRs) were originally identified by their abilities to recognize different forms of modified low-density lipoproteins (LDLs) with broad binding specificities [1,2,3,4]
The fluorescent images showed that L-ferritin co-localized with SCARA5 on the transfected cells, but no L-ferritin was found on the SCARA5DSRCR-transfected cells (Fig. 1D), suggesting that the scavenger receptor cysteine-rich (SRCR) domain could mediate the uptake of L-ferritin
The FLAG tag pulldown results showed that the intact ectodomain and the SRCR domain alone could pull down L-ferritin directly, but no L-ferritin was detected using the ectodomain without the SRCR portion (Fig. 1C), confirming that the SRCR domain is the binding domain of L-ferritin on SCARA5
Summary
Scavenger receptors (SRs) were originally identified by their abilities to recognize different forms of modified low-density lipoproteins (LDLs) with broad binding specificities [1,2,3,4]. SR class A (SR-A) has five known members, including SCARA1 (SR-A1, CD204, MSR1, SR-AI, etc.), MARCO (SRA2, SCARA2), SCARA3 (CSR), SCARA4 (SRCL), and SCARA5 (TESR) [11, 12] They are type II transmembrane proteins with similar domain arrangement, containing an N-terminal cytoplasmic region followed by a transmembrane helix and a large C-terminal extracellular portion. Many aspects of serum ferritin remain unclear, evidence has shown that it might be involved in iron delivery [15, 42, 43], angiogenesis [44,45,46], inflammation, immunity, and cancer [47] It could act as an inflammatory marker and is associated with a variety of diseases, including acute respiratory distress syndrome [48], ALS [49], and atherosclerosis
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