Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor.
Albumin is the most abundant protein in blood where it has a pivotal role as a transporter of fatty acids and drugs. Like IgG, albumin has long serum half-life, protected from degradation by pH-dependent recycling mediated by interaction with the neonatal Fc receptor, FcRn. Although the FcRn interaction with IgG is well characterized at the atomic level, its interaction with albumin is not. Here we present structure-based modelling of the FcRn-albumin complex, supported by binding analysis of site-specific mutants, providing mechanistic evidence for the presence of pH-sensitive ionic networks at the interaction interface. These networks involve conserved histidines in both FcRn and albumin domain III. Histidines also contribute to intramolecular interactions that stabilize the otherwise flexible loops at both the interacting surfaces. Molecular details of the FcRn-albumin complex may guide the development of novel albumin variants with altered serum half-life as carriers of drugs.
Centre for Immune Regulation and Department of Molecular Biosciences, University of Oslo, Oslo N-0316, Norway. j.t.andersen@imbv.uio.no
Jan Terje
JT
Andersen
Bjørn
B
Dalhus
Jason
J
Cameron
Muluneh Bekele
MB
Daba
Andrew
A
Plumridge
Leslie
L
Evans
Stephan O
SO
Brennan
Kristin Støen
KS
Gunnarsen
Magnar
M
Bjørås
Darrell
D
Sleep
Inger
I
Sandlie
D000418:Albumins / Q000737:chemistry*; D001665:Binding Sites; D004926:Escherichia coli / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000737:chemistry; D007477:Ions; D008958:Models, Molecular; D008968:Molecular Conformation; D016296:Mutagenesis; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017434:Protein Structure, Tertiary; D011961:Receptors, Fc / Q000737:chemistry* / Q000235:genetics*; D012709:Serum Albumin / Q000737:chemistry; D013997:Time Factors
D000418:Albumins; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D007477:Ions; D011961:Receptors, Fc; D012709:Serum Albumin; D006639:Histidine; C100688:Fc receptor, neonatal