Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor

Jan Terje Andersen (), Bjørn Dalhus, Jason Cameron, Muluneh Bekele Daba, Andrew Plumridge, Leslie Evans, Stephan O. Brennan, Kristin Støen Gunnarsen, Magnar Bjørås, Darrell Sleep and Inger Sandlie
Additional contact information
Jan Terje Andersen: University of Oslo
Bjørn Dalhus: Oslo University Hospital Rikshospitalet and University of Oslo, PO Box 4950, Nydalen, Oslo N-0424, Norway.
Jason Cameron: Novozymes Biopharma UK Ltd., Castle Court, 59 Castle Boulevard, Nottingham NG7 1FD, UK.
Muluneh Bekele Daba: University of Oslo
Andrew Plumridge: Novozymes Biopharma UK Ltd., Castle Court, 59 Castle Boulevard, Nottingham NG7 1FD, UK.
Leslie Evans: Novozymes Biopharma UK Ltd., Castle Court, 59 Castle Boulevard, Nottingham NG7 1FD, UK.
Stephan O. Brennan: Molecular Pathology Laboratory, Christchurch School of Medicine and Health Sciences, University of Otago, PO Box 8140, Christchurch, New Zealand.
Kristin Støen Gunnarsen: University of Oslo
Magnar Bjørås: Oslo University Hospital Rikshospitalet and University of Oslo, PO Box 4950, Nydalen, Oslo N-0424, Norway.
Darrell Sleep: Novozymes Biopharma UK Ltd., Castle Court, 59 Castle Boulevard, Nottingham NG7 1FD, UK.
Inger Sandlie: University of Oslo

Nature Communications, 2012, vol. 3, issue 1, 1-9

Abstract: Abstract 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.

Date: 2012
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DOI: 10.1038/ncomms1607

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