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

摘要

Albumin is the most abundant protein in blood where it has a pivotal role as a transporter offatty acids and drugs. Like IgG, albumin has long serum half-life, protected from degradation bypH-dependent recycling mediated by interaction with the neonatal Fc receptor, FcRn. Althoughthe FcRn interaction with IgG is well characterized at the atomic level, its interaction withalbumin is not. Here we present structure-based modelling of the FcRn – albumin complex,supported by binding analysis of site-specific mutants, providing mechanistic evidence forthe presence of pH-sensitive ionic networks at the interaction interface. These networksinvolve conserved histidines in both FcRn and albumin domain III. Histidines also contributeto intramolecular interactions that stabilize the otherwise flexible loops at both the interactingsurfaces. Molecular details of the FcRn – albumin complex may guide the development of novelalbumin variants with altered serum half-life as carriers of drugs.