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

被引：164

作者：

Andersen, Jan Terje ^{[1
,2
,3
,4
]}

Dalhus, Bjorn ^{[3
,5
,6
,7
]}

Cameron, Jason ^{[8
]}

Daba, Muluneh Bekele ^{[1
,2
,3
,4
]}

Plumridge, Andrew ^{[8
]}

Evans, Leslie ^{[8
]}

Brennan, Stephan O. ^{[9
]}

Gunnarsen, Kristin Stoen ^{[1
,2
,3
,4
]}

Bjoras, Magnar ^{[3
,5
,6
,7
]}

Sleep, Darrell ^{[8
]}

Sandlie, Inger ^{[1
,2
,3
,4
]}

机构：

[1] Univ Oslo, CIR, N-0316 Oslo, Norway

[2] Univ Oslo, Dept Mol Biosci, N-0316 Oslo, Norway

[3] Univ Oslo, N-0424 Oslo, Norway

[4] Natl Hosp Norway, Oslo Univ Hosp, Dept Immunol, CIR, N-0424 Oslo, Norway

[5] Natl Hosp Norway, Oslo Univ Hosp, CMBN, N-0424 Oslo, Norway

[6] Natl Hosp Norway, Oslo Univ Hosp, Dept Microbiol, N-0424 Oslo, Norway

[7] Natl Hosp Norway, Oslo Univ Hosp, Dept Med Biochem, N-0424 Oslo, Norway

[8] Novozymes Biopharma UK Ltd, Nottingham NG7 1FD, England

[9] Univ Otago, Christchurch Sch Med & Hlth Sci, Mol Pathol Lab, Christchurch, New Zealand

来源：

NATURE COMMUNICATIONS | 2012年 / 3卷

关键词：

HUMAN SERUM-ALBUMIN; SACCHAROMYCES-CEREVISIAE STRAINS; I-RELATED RECEPTOR; CRYSTAL-STRUCTURE; HETEROLOGOUS PROTEINS; ANTIBODY FRAGMENTS; IGG HOMEOSTASIS; COMPLEX; PHARMACOKINETICS; THERAPEUTICS;

D O I：

10.1038/ncomms1607

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：9

共 45 条

[1]

Ligand binding and antigenic properties of a human neonatal Fc receptor with mutation of two unpaired cysteine residues [J].