Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface
The long circulating half-life of serum albumin, the most abundant protein in mammalian plasma, derives from pH-dependent endosomal salvage from degradation, mediated by the neonatal Fc receptor (FcRn). Using yeast display, we identified human serum albumin (HSA) variants with increased affinity for...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier B.V.
2014
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| Online Access: | http://hdl.handle.net/1721.1/91612 https://orcid.org/0000-0003-2398-5896 |
| _version_ | 1811078031924527104 |
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| author | Schmidt, Michael M. Townson, Sharon A. Andreucci, Amy J. King, Bracken Matheny Schirmer, Emily B. Murillo, Alec J. Dombrowski, Christian Tisdale, Alison W. Lowden, Patricia A. Masci, Allyson L. Kovalchin, Joseph T. Erbe, David V. Wittrup, Karl Dane Furfine, Eric S. Barnes, Thomas M. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Schmidt, Michael M. Townson, Sharon A. Andreucci, Amy J. King, Bracken Matheny Schirmer, Emily B. Murillo, Alec J. Dombrowski, Christian Tisdale, Alison W. Lowden, Patricia A. Masci, Allyson L. Kovalchin, Joseph T. Erbe, David V. Wittrup, Karl Dane Furfine, Eric S. Barnes, Thomas M. |
| author_sort | Schmidt, Michael M. |
| collection | MIT |
| description | The long circulating half-life of serum albumin, the most abundant protein in mammalian plasma, derives from pH-dependent endosomal salvage from degradation, mediated by the neonatal Fc receptor (FcRn). Using yeast display, we identified human serum albumin (HSA) variants with increased affinity for human FcRn at endosomal pH, enabling us to solve the crystal structure of a variant HSA/FcRn complex. We find an extensive, primarily hydrophobic interface stabilized by hydrogen-bonding networks involving protonated histidines internal to each protein. The interface features two key FcRn tryptophan side chains inserting into deep hydrophobic pockets on HSA that overlap albumin ligand binding sites. We find that fatty acids (FAs) compete with FcRn, revealing a clash between ligand binding and recycling, and that our high-affinity HSA variants have significantly increased circulating half-lives in mice and monkeys. These observations open the way for the creation of biotherapeutics with significantly improved pharmacokinetics. |
| first_indexed | 2024-09-23T10:52:19Z |
| format | Article |
| id | mit-1721.1/91612 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:52:19Z |
| publishDate | 2014 |
| publisher | Elsevier B.V. |
| record_format | dspace |
| spelling | mit-1721.1/916122021-09-10T15:13:24Z Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface Schmidt, Michael M. Townson, Sharon A. Andreucci, Amy J. King, Bracken Matheny Schirmer, Emily B. Murillo, Alec J. Dombrowski, Christian Tisdale, Alison W. Lowden, Patricia A. Masci, Allyson L. Kovalchin, Joseph T. Erbe, David V. Wittrup, Karl Dane Furfine, Eric S. Barnes, Thomas M. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Wittrup, Karl Dane The long circulating half-life of serum albumin, the most abundant protein in mammalian plasma, derives from pH-dependent endosomal salvage from degradation, mediated by the neonatal Fc receptor (FcRn). Using yeast display, we identified human serum albumin (HSA) variants with increased affinity for human FcRn at endosomal pH, enabling us to solve the crystal structure of a variant HSA/FcRn complex. We find an extensive, primarily hydrophobic interface stabilized by hydrogen-bonding networks involving protonated histidines internal to each protein. The interface features two key FcRn tryptophan side chains inserting into deep hydrophobic pockets on HSA that overlap albumin ligand binding sites. We find that fatty acids (FAs) compete with FcRn, revealing a clash between ligand binding and recycling, and that our high-affinity HSA variants have significantly increased circulating half-lives in mice and monkeys. These observations open the way for the creation of biotherapeutics with significantly improved pharmacokinetics. 2014-11-19T19:03:38Z 2014-11-19T19:03:38Z 2013-11 2013-08 Article http://purl.org/eprint/type/JournalArticle 09692126 http://hdl.handle.net/1721.1/91612 Schmidt, Michael M., Sharon A. Townson, Amy J. Andreucci, Bracken M. King, Emily B. Schirmer, Alec J. Murillo, Christian Dombrowski, et al. “Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface.” Structure 21, no. 11 (November 2013): 1966–1978. © 2013 Elsevier Ltd. https://orcid.org/0000-0003-2398-5896 en_US http://dx.doi.org/10.1016/j.str.2013.08.022 Structure Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/msword Elsevier B.V. Elsevier Open Archive |
| spellingShingle | Schmidt, Michael M. Townson, Sharon A. Andreucci, Amy J. King, Bracken Matheny Schirmer, Emily B. Murillo, Alec J. Dombrowski, Christian Tisdale, Alison W. Lowden, Patricia A. Masci, Allyson L. Kovalchin, Joseph T. Erbe, David V. Wittrup, Karl Dane Furfine, Eric S. Barnes, Thomas M. Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface |
| title | Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface |
| title_full | Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface |
| title_fullStr | Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface |
| title_full_unstemmed | Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface |
| title_short | Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface |
| title_sort | crystal structure of an hsa fcrn complex reveals recycling by competitive mimicry of hsa ligands at a ph dependent hydrophobic interface |
| url | http://hdl.handle.net/1721.1/91612 https://orcid.org/0000-0003-2398-5896 |
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