Journal of Molecular Medicine

, Volume 91, Issue 6, pp 759–770

Single-stranded nucleic acids promote SAMHD1 complex formation

  • Victoria Tüngler
  • Wolfgang Staroske
  • Barbara Kind
  • Manuela Dobrick
  • Stefanie Kretschmer
  • Franziska Schmidt
  • Claudia Krug
  • Mike Lorenz
  • Osvaldo Chara
  • Petra Schwille
  • Min Ae Lee-Kirsch
Original Article

DOI: 10.1007/s00109-013-0995-3

Cite this article as:
Tüngler, V., Staroske, W., Kind, B. et al. J Mol Med (2013) 91: 759. doi:10.1007/s00109-013-0995-3

Abstract

SAM domain and HD domain-containing protein 1 (SAMHD1) is a dGTP-dependent triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs) thereby limiting the intracellular dNTP pool. Mutations in SAMHD1 cause Aicardi–Goutières syndrome (AGS), an inflammatory encephalopathy that mimics congenital viral infection and that phenotypically overlaps with the autoimmune disease systemic lupus erythematosus. Both disorders are characterized by activation of the antiviral cytokine interferon-α initiated by immune recognition of self nucleic acids. Here we provide first direct evidence that SAMHD1 associates with endogenous nucleic acids in situ. Using fluorescence cross-correlation spectroscopy, we demonstrate that SAMHD1 specifically interacts with ssRNA and ssDNA and establish that nucleic acid-binding and formation of SAMHD1 complexes are mutually dependent. Interaction with nucleic acids and complex formation do not require the SAM domain, but are dependent on the HD domain and the C-terminal region of SAMHD1. We finally demonstrate that mutations associated with AGS exhibit both impaired nucleic acid-binding and complex formation implicating that interaction with nucleic acids is an integral aspect of SAMHD1 function.

Keywords

SAMHD1 Aicardi–Goutières syndrome Fluorescence cross-correlation spectroscopy Nucleic acids 

Supplementary material

109_2013_995_MOESM1_ESM.pdf (624 kb)
ESM 1(PDF 623 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Victoria Tüngler
    • 1
  • Wolfgang Staroske
    • 2
  • Barbara Kind
    • 1
  • Manuela Dobrick
    • 1
  • Stefanie Kretschmer
    • 1
  • Franziska Schmidt
    • 1
  • Claudia Krug
    • 1
  • Mike Lorenz
    • 3
  • Osvaldo Chara
    • 4
    • 5
  • Petra Schwille
    • 2
    • 6
  • Min Ae Lee-Kirsch
    • 1
  1. 1.Children’s HospitalTechnical University DresdenDresdenGermany
  2. 2.Biotechnology CenterTechnical University DresdenDresdenGermany
  3. 3.Max Planck Institute of Molecular Cell Biology and GeneticsDresdenGermany
  4. 4.Center for Information Services and High Performance ComputingTechnical University DresdenDresdenGermany
  5. 5.Institute of Physics of Liquids and Biological Systems (IFLYSIB), CONICETNational University of La PlataLa PlataArgentina
  6. 6.Max Planck Institute of BiochemistryMartinsriedGermany

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