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Molecular basis for retinol binding by serum amyloid A during infection

Serum amyloid A (SAA) proteins are strongly induced in the liver by systemic infection and in the intestine by bacterial colonization. In infected mice, SAA proteins circulate in association with the vitamin A derivative retinol, suggesting that SAAs transport retinol during infection. Here we illum...

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Autores principales: Hu, Zehan, Bang, Ye-Ji, Ruhn, Kelly A., Hooper, Lora V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754605/
https://www.ncbi.nlm.nih.gov/pubmed/31484771
http://dx.doi.org/10.1073/pnas.1910713116
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author Hu, Zehan
Bang, Ye-Ji
Ruhn, Kelly A.
Hooper, Lora V.
author_facet Hu, Zehan
Bang, Ye-Ji
Ruhn, Kelly A.
Hooper, Lora V.
author_sort Hu, Zehan
collection PubMed
description Serum amyloid A (SAA) proteins are strongly induced in the liver by systemic infection and in the intestine by bacterial colonization. In infected mice, SAA proteins circulate in association with the vitamin A derivative retinol, suggesting that SAAs transport retinol during infection. Here we illuminate a structural basis for the retinol–SAA interaction. In the bloodstream of infected mice, most SAA is complexed with high-density lipoprotein (HDL). However, we found that the majority of the circulating retinol was associated with the small fraction of SAA proteins that circulate without binding to HDL, thus identifying free SAA as the predominant retinol-binding form in vivo. We then determined the crystal structure of retinol-bound mouse SAA3 at a resolution of 2.2 Å. Retinol-bound SAA3 formed a novel asymmetric trimeric assembly that was generated by the hydrophobic packing of the conserved amphipathic helices α1 and α3. This hydrophobic packing created a retinol-binding pocket in the center of the trimer, which was confirmed by mutagenesis studies. Together, these findings illuminate the molecular basis for retinol transport by SAA proteins during infection.
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spelling pubmed-67546052019-10-01 Molecular basis for retinol binding by serum amyloid A during infection Hu, Zehan Bang, Ye-Ji Ruhn, Kelly A. Hooper, Lora V. Proc Natl Acad Sci U S A Biological Sciences Serum amyloid A (SAA) proteins are strongly induced in the liver by systemic infection and in the intestine by bacterial colonization. In infected mice, SAA proteins circulate in association with the vitamin A derivative retinol, suggesting that SAAs transport retinol during infection. Here we illuminate a structural basis for the retinol–SAA interaction. In the bloodstream of infected mice, most SAA is complexed with high-density lipoprotein (HDL). However, we found that the majority of the circulating retinol was associated with the small fraction of SAA proteins that circulate without binding to HDL, thus identifying free SAA as the predominant retinol-binding form in vivo. We then determined the crystal structure of retinol-bound mouse SAA3 at a resolution of 2.2 Å. Retinol-bound SAA3 formed a novel asymmetric trimeric assembly that was generated by the hydrophobic packing of the conserved amphipathic helices α1 and α3. This hydrophobic packing created a retinol-binding pocket in the center of the trimer, which was confirmed by mutagenesis studies. Together, these findings illuminate the molecular basis for retinol transport by SAA proteins during infection. National Academy of Sciences 2019-09-17 2019-09-04 /pmc/articles/PMC6754605/ /pubmed/31484771 http://dx.doi.org/10.1073/pnas.1910713116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Hu, Zehan
Bang, Ye-Ji
Ruhn, Kelly A.
Hooper, Lora V.
Molecular basis for retinol binding by serum amyloid A during infection
title Molecular basis for retinol binding by serum amyloid A during infection
title_full Molecular basis for retinol binding by serum amyloid A during infection
title_fullStr Molecular basis for retinol binding by serum amyloid A during infection
title_full_unstemmed Molecular basis for retinol binding by serum amyloid A during infection
title_short Molecular basis for retinol binding by serum amyloid A during infection
title_sort molecular basis for retinol binding by serum amyloid a during infection
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754605/
https://www.ncbi.nlm.nih.gov/pubmed/31484771
http://dx.doi.org/10.1073/pnas.1910713116
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