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Crystal structure of the scavenger receptor cysteine-rich domain 5 (SRCR5) from porcine CD163
Structural highlights
FunctionC163A_PIG Involved in clearance and endocytosis of hemoglobin/haptoglobin complexes by macrophages and may thereby protect tissues from free hemoglobin-mediated oxidative damage. May play a role in the uptake and recycling of iron, via endocytosis of hemoglobin/haptoglobin and subsequent breakdown of heme. Binds hemoglobin/haptoglobin complexes in a calcium-dependent and pH-dependent manner. Induces a cascade of intracellular signals that involves tyrosine kinase-dependent calcium mobilization, inositol triphosphate production and secretion of IL6 and CSF1 (By similarity). May play a role in the process of infection of porcine monocytes/macrophages by African swine fever virus (ASFV). In case of porcine reproductive and respiratory syndrome virus (PRRSV), serves mediates virion attachment and plays a role in viral entry.[1] After shedding, the soluble form (sCD163) may play an anti-inflammatory role. Publication Abstract from PubMedPorcine reproductive and respiratory syndrome (PRRS) has become an economically critical factor in swine industry since its worldwide spread in the 1990s. Infection by its causative agent, PRRS virus (PRRSV), was proven to be mediated by an indispensable receptor, porcine CD163 (pCD163), and the fifth scavenger receptor cysteine-rich domain (SRCR5) is essential for virus infection. However, the structural details and specific residues of pCD163 SRCR5 involved in infection have not been defined yet. In this study, we prepared recombinant pCD163 SRCR5 in Drosophila melanogaster Schneider 2 (S2) cells and determined its crystal structure at a high resolution of 2.0 A. This structure includes a markedly long loop region and shows a special electrostatic potential, and these are significantly different from those of other members of the scavenger receptor cysteine-rich superfamily (SRCR-SF). Subsequently, we carried out structure-based mutational studies to identify that the arginine residue at position 561 (Arg561) in the long loop region is important for PRRSV infection. Further, we showed Arg561 probably takes effect on the binding of pCD163 to PRRSV during virus invasion. Altogether the current work provides the first view of the CD163 SRCR domain, expands our knowledge of the invasion mechanism of PRRSV, and supports a molecular basis for prevention and control of the virus. IMPORTANCE: PRRS has caused huge economic losses to pig farming. The syndrome is caused by PRRSV, and PRRSV infection has been shown to be mediated by host cell surface receptors. One of them, pCD163, is especially indispensable, and its SRCR5 domain has been further demonstrated to play a significant role in virus infection. However, its structural details and the residues involved in infection are unknown. In this study, we determined the crystal structure of pCD163 SRCR5 and then carried out site-directed mutational studies based on the crystal structure to elucidate which residue is important. Our work not only provides structural information on the CD163 SRCR domain for the first time but also indicates the molecular mechanism of PRRSV infection and lays a foundation for future applications in prevention and control of PRRS. The Crystal Structure of the Fifth Scavenger Receptor Cysteine-Rich Domain of Porcine CD163 Reveals an Important Residue Involved in Porcine Reproductive and Respiratory Syndrome Virus Infection.,Ma H, Jiang L, Qiao S, Zhi Y, Chen XX, Yang Y, Huang X, Huang M, Li R, Zhang GP J Virol. 2017 Jan 18;91(3). pii: e01897-16. doi: 10.1128/JVI.01897-16. Print 2017, Feb 1. PMID:27881657[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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