title: The X-Ray Crystallographic Structure of the Human Neonatal Fc Receptor at Acidic pH Gives Insights into pH-Dependent Conformational Changes.
abstract: High levels of circulating immunoglobulin G (IgG) and serum albumin (SA) are maintained through recycling by the neonatal Fc receptor (FcRn). FcRn interacts with IgG and SA in a pHdependent manner and rescues them from lysosomal degradation. We have determined the crystal structure of extracellular domain of human FcRn, a heterodimeric complex of α-chain and β2- microglobulin, at pH 4.5. The structure was compared with the previously reported unliganded human FcRn structure at pH 8.5 and complex structures of FcRn bound to SA and/or Fc determined at acidic pHs. Structural differences are more pronounced between the two unliganded FcRn structures at pH 4.5 and pH 8.5 than between unliganded FcRn and the complex structures at acidic pHs. At acidic pH, protonation of H166 induces interactions with E54 and Y60 stabilizing the "WW loop" important for SA binding, and H161 interacts with E165 causing conformational changes of helix 3. These structural changes make the FcRn amenable for binding with SA at acidic pH. The Fc binding surface does not show any major main chain differences between the unliganded structures at pH 8.5 and pH 4.5. Side chain changes upon Fc binding were observed when compared with the complex structures. This suggests that major structural differences observed between unliganded and ligand bound structures are primarily due to pH changes rather than ligand binding.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Taha
authors.forename: Sally E
authors.initials: SE
authors.lastname: Ward
authors.affiliation: Department of Bioengineering, The University of Texas at Dallas, 800 W. Campbell Rd, RL10, Richardson, USA. hnam@utdallas.edu.
authors.forename: Hyun-Joo
authors.initials: HJ
authors.lastname: Nam
mesh_terms: D018360:Crystallography, X-Ray; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism*; D007074:Immunoglobulin G / Q000097:blood; D017433:Protein Structure, Secondary; D011961:Receptors, Fc / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011961:Receptors, Fc; D012709:Serum Albumin; C100688:Fc receptor, neonatal