Serum amyloid A is a retinol binding protein that transports retinol during bacterial infection

  1. Mehabaw G Derebe
  2. Clare M Zlatkov
  3. Sureka Gattu
  4. Kelly A Ruhn
  5. Shipra Vaishnava
  6. Gretchen E Diehl
  7. John B MacMillan
  8. Noelle S Williams
  9. Lora V Hooper  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. New York University School of Medicine, United States

Abstract

Retinol plays a vital role in the immune response to infection, yet proteins that mediate retinol transport during infection have not been identified. Serum amyloid A (SAA) proteins are strongly induced in the liver by systemic infection and in the intestine by bacterial colonization, but their exact functions remain unclear. Here we show that mouse and human SAAs are retinol binding proteins. Mouse and human SAAs bound retinol with nanomolar affinity, were associated with retinol in vivo, and limited the bacterial burden in tissues after acute infection. We determined the crystal structure of mouse SAA3 at a resolution of 2 Å, finding that it forms a tetramer with a hydrophobic binding pocket that can accommodate retinol. Our results thus identify SAAs as a family of microbe-inducible retinol binding proteins, reveal a unique protein architecture involved in retinol binding, and suggest how retinol is circulated during infection.

Article and author information

Author details

  1. Mehabaw G Derebe

    University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Clare M Zlatkov

    University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sureka Gattu

    University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kelly A Ruhn

    University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Shipra Vaishnava

    University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Gretchen E Diehl

    New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. John B MacMillan

    University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Noelle S Williams

    University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Lora V Hooper

    University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    lora.hooper@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Animal subjects research approved by all animal experiments were approved by the Institutional Animal Care and Research Advisory Committee at the University of Texas Southwestern Medical Center, and the approved animal protocol number is 2011-0197. The institutional guidelines for the care and use of laboratory animals were followed.

Reviewing Editor

  1. Fiona M Powrie, Oxford University, United Kingdom

Publication history

  1. Received: April 26, 2014
  2. Accepted: July 28, 2014
  3. Accepted Manuscript published: July 29, 2014 (version 1)
  4. Version of Record published: August 12, 2014 (version 2)

Copyright

© 2014, Derebe et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,011
    Page views
  • 685
    Downloads
  • 82
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Mehabaw G Derebe
  2. Clare M Zlatkov
  3. Sureka Gattu
  4. Kelly A Ruhn
  5. Shipra Vaishnava
  6. Gretchen E Diehl
  7. John B MacMillan
  8. Noelle S Williams
  9. Lora V Hooper
(2014)
Serum amyloid A is a retinol binding protein that transports retinol during bacterial infection
eLife 3:e03206.
https://doi.org/10.7554/eLife.03206
  1. Further reading

Further reading

    1. Structural Biology and Molecular Biophysics
    Maicon Landim-Vieira et al.
    Research Article Updated

    Phosphorylation and acetylation of sarcomeric proteins are important for fine-tuning myocardial contractility. Here, we used bottom-up proteomics and label-free quantification to identify novel post-translational modifications (PTMs) on β-myosin heavy chain (β-MHC) in normal and failing human heart tissues. We report six acetylated lysines and two phosphorylated residues: K34-Ac, K58-Ac, S210-P, K213-Ac, T215-P, K429-Ac, K951-Ac, and K1195-Ac. K951-Ac was significantly reduced in both ischemic and nonischemic failing hearts compared to nondiseased hearts. Molecular dynamics (MD) simulations show that K951-Ac may impact stability of thick filament tail interactions and ultimately myosin head positioning. K58-Ac altered the solvent-exposed SH3 domain surface – known for protein–protein interactions – but did not appreciably change motor domain conformation or dynamics under conditions studied. Together, K213-Ac/T215-P altered loop 1’s structure and dynamics – known to regulate ADP-release, ATPase activity, and sliding velocity. Our study suggests that β-MHC acetylation levels may be influenced more by the PTM location than the type of heart disease since less protected acetylation sites are reduced in both heart failure groups. Additionally, these PTMs have potential to modulate interactions between β-MHC and other regulatory sarcomeric proteins, ADP-release rate of myosin, flexibility of the S2 region, and cardiac myofilament contractility in normal and failing hearts.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Atefeh Rafiei et al.
    Research Article Updated

    Doublecortin (DCX) is a microtubule (MT)-associated protein that regulates MT structure and function during neuronal development and mutations in DCX lead to a spectrum of neurological disorders. The structural properties of MT-bound DCX that explain these disorders are incompletely determined. Here, we describe the molecular architecture of the DCX–MT complex through an integrative modeling approach that combines data from X-ray crystallography, cryo-electron microscopy, and a high-fidelity chemical crosslinking method. We demonstrate that DCX interacts with MTs through its N-terminal domain and induces a lattice-dependent self-association involving the C-terminal structured domain and its disordered tail, in a conformation that favors an open, domain-swapped state. The networked state can accommodate multiple different attachment points on the MT lattice, all of which orient the C-terminal tails away from the lattice. As numerous disease mutations cluster in the C-terminus, and regulatory phosphorylations cluster in its tail, our study shows that lattice-driven self-assembly is an important property of DCX.