dc.date.accessioned | 2017-03-07T16:32:04Z | |
dc.date.available | 2017-03-07T16:32:04Z | |
dc.date.created | 2014-11-03T13:26:55Z | |
dc.date.issued | 2014 | |
dc.identifier.citation | Sand, Kine Marita Knudsen Dalhus, Bjørn Christianson, Gregory J. Bern, Malin C. Foss, Stian Cameron, Jason Sleep, Darrell Bjørås, Magnar Roopenian, Derry C Sandlie, Inger Andersen, Jan Terje . Dissection of the neonatal Fc receptor (FcRn)-albumin interface using mutagenesis and anti-FcRn albumin-blocking antibodies. Journal of Biological Chemistry. 2014, 289(24), 17228-17239 | |
dc.identifier.uri | http://hdl.handle.net/10852/54507 | |
dc.description.abstract | Albumin is the most abundant protein in blood and plays a pivotal role as a multitransporter of a wide range of molecules such as fatty acids, metabolites, hormones, and toxins. In addition, it binds a variety of drugs. Its role as distributor is supported by its extraordinary serum half-life of 3 weeks. This is related to its size and binding to the cellular receptor FcRn, which rescues albumin from intracellular degradation. Furthermore, the long half-life has fostered a great and increasing interest in utilization of albumin as a carrier of protein therapeutics and chemical drugs. However, to fully understand how FcRn acts as a regulator of albumin homeostasis and to take advantage of the FcRn-albumin interaction in drug design, the interaction interface needs to be dissected. Here, we used a panel of monoclonal antibodies directed towards human FcRn in combination with site-directed mutagenesis and structural modeling to unmask the binding sites for albumin blocking antibodies and albumin on the receptor, which revealed that the interaction is not only strictly pH-dependent, but predominantly hydrophobic in nature. Specifically, we provide mechanistic evidence for a crucial role of a cluster of conserved tryptophan residues that expose a pH-sensitive loop of FcRn, and identify structural differences in proximity to these hot spot residues that explain divergent cross-species binding properties of FcRn. Our findings expand our knowledge of how FcRn is controlling albumin homeostasis at a molecular level, which will guide design and engineering of novel albumin variants with altered transport properties.
This research was originally published in: Journal of Biological Chemistry. © the American Society for Biochemistry and Molecular Biology. | en_US |
dc.language | EN | |
dc.title | Dissection of the neonatal Fc receptor (FcRn)-albumin interface using mutagenesis and anti-FcRn albumin-blocking antibodies | en_US |
dc.type | Journal article | en_US |
dc.creator.author | Sand, Kine Marita Knudsen | |
dc.creator.author | Dalhus, Bjørn | |
dc.creator.author | Christianson, Gregory J. | |
dc.creator.author | Bern, Malin C. | |
dc.creator.author | Foss, Stian | |
dc.creator.author | Cameron, Jason | |
dc.creator.author | Sleep, Darrell | |
dc.creator.author | Bjørås, Magnar | |
dc.creator.author | Roopenian, Derry C | |
dc.creator.author | Sandlie, Inger | |
dc.creator.author | Andersen, Jan Terje | |
cristin.unitcode | 185,53,2,11 | |
cristin.unitname | Senter for immunregulering | |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |
dc.identifier.cristin | 1169366 | |
dc.identifier.bibliographiccitation | info:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Journal of Biological Chemistry&rft.volume=289&rft.spage=17228&rft.date=2014 | |
dc.identifier.jtitle | Journal of Biological Chemistry | |
dc.identifier.volume | 289 | |
dc.identifier.issue | 24 | |
dc.identifier.startpage | 17228 | |
dc.identifier.endpage | 17239 | |
dc.identifier.doi | http://dx.doi.org/10.1074/jbc.M113.522565 | |
dc.identifier.urn | URN:NBN:no-57624 | |
dc.type.document | Tidsskriftartikkel | en_US |
dc.type.peerreviewed | Peer reviewed | |
dc.source.issn | 0021-9258 | |
dc.identifier.fulltext | Fulltext https://www.duo.uio.no/bitstream/handle/10852/54507/1/13.%2Bzbc17228.pdf | |
dc.type.version | PublishedVersion | |