Interactions of ferritin with scavenger receptor class A members

J Biol Chem. 2020 Nov 13;295(46):15727-15741. doi: 10.1074/jbc.RA120.014690. Epub 2020 Sep 9.


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.

Keywords: SCARA5; SR class A; SRCR domain; X-ray crystallography; cell surface receptor; ferritin; protein structure; scavenger receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Calcium / chemistry
  • Calcium / metabolism
  • Crystallography, X-Ray
  • Ferritins / metabolism*
  • Humans
  • Kinetics
  • Macrophages / cytology
  • Macrophages / metabolism
  • Mice
  • Molecular Dynamics Simulation
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Protein Domains
  • Protein Structure, Tertiary
  • Scavenger Receptors, Class A / chemistry
  • Scavenger Receptors, Class A / genetics
  • Scavenger Receptors, Class A / metabolism*


  • SCARA5 protein, human
  • SCARA5 protein, mouse
  • Scavenger Receptors, Class A
  • Ferritins
  • Calcium

Associated data

  • PDB/2FFX
  • PDB/6J02