INVESTIGADORES
CHARA Osvaldo
artículos
Título:
Single-stranded nucleic acids promote SAMHD1 complex formation
Autor/es:
TÜNGLER VICTORIA; STAROSKE WOLFGANG ; KIND BARBARA; DOBRICK MANUELA; KRETSCHMER STEFANIE; SCHMIDT FRANZISKA; KRUG CLAUDIA; LORENZ MIKE; CHARA OSVALDO; SCHWILLE PETRA; LEE-KIRSCH MIN AE
Revista:
JOURNAL OF MOLECULAR MEDICINE (BERLIN, GERMANY)
Editorial:
SPRINGER
Referencias:
Lugar: Berlin; Año: 2013 vol. 91 p. 759 - 770
ISSN:
0946-2716
Resumen:
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.