Single-stranded nucleic acids promote SAMHD1 complex formation

Authors
Tuengler, Victoria; Wolfgang, Staroske; Kind, Barbara; Dobrick, Manuela; Kretschmer, Stefanie; Schmidt, Franziska; Krug, Claudia; Lorenz, Mike; Chara, Osvaldo; Schwille, Petra; Lee-Kirsch, Min Ae
Publication Year
2013
Language
English
Format
article
Status
Published version
Description
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.
Fil: Tuengler, Victoria. Technische Universität Dresden; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Wolfgang, Staroske. Technische Universität Dresden; Alemania
Fil: Kind, Barbara. Technische Universität Dresden; Alemania
Fil: Dobrick, Manuela. Technische Universität Dresden; Alemania
Fil: Kretschmer, Stefanie. Technische Universität Dresden; Alemania
Fil: Schmidt, Franziska. Technische Universität Dresden; Alemania
Fil: Krug, Claudia. Technische Universität Dresden; Alemania
Fil: Lorenz, Mike. Max Planck Institute of Molecular Cell Biology and Genetics; Alemania
Fil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Technische Universität Dresden; Alemania
Fil: Schwille, Petra. Max Planck Institute Of Biochemistry; Alemania
Fil: Lee-Kirsch, Min Ae. Technische Universität Dresden; Alemania
Subject
SAMHD1
Aicardi–Goutières syndrome
Fluorescence cross-correlation spectroscopy
Nucleic acids
Bioquímica y Biología Molecular
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/24122