TY  - JOUR
AU  - Motz, C.
AU  - Schuhmann, K. M.
AU  - Kirchhofer, A.
AU  - Moldt, M.
AU  - Witte, G.
AU  - Conzelmann, K.-K.
AU  - Hopfner, K.-P.
AU  - DESY
TI  - Paramyxovirus V Proteins Disrupt the Fold of the RNA Sensor MDA5 to Inhibit Antiviral Signaling
JO  - Science
VL  - 339
SN  - 0036-8075
M1  - PHPPUBDB-24959
SP  - 693
PY  - 2013
N1  - Post referee fulltext in progress; Embargo 6 months from publication 
AB  - The retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) melanoma differentiation-associated protein 5 (MDA5) senses cytoplasmic viral RNA and activates antiviral innate immunity. To reveal how paramyxoviruses counteract this response, we determined the crystal structure of the MDA5 adenosine 5'-triphosphate (ATP)-hydrolysis domain in complex with the viral inhibitor V protein. The V protein unfolded the ATP-hydrolysis domain of MDA5 via a β-hairpin motif and recognized a structural motif of MDA5 that is normally buried in the conserved helicase fold. This leads to disruption of the MDA5 ATP-hydrolysis site and prevention of RNA-bound MDA5 filament formation. The structure explains why V proteins inactivate MDA5, but not RIG-I, and mutating only two amino acids in RIG-I induces robust V protein binding. Our results suggest an inhibition mechanism of RLR signalosome formation by unfolding of receptor and inhibitor.
KW  - Adenosine Triphosphate: metabolism
KW  - Amino Acid Motifs
KW  - Amino Acid Sequence
KW  - Animals
KW  - Crystallography, X-Ray
KW  - DEAD-box RNA Helicases: chemistry
KW  - DEAD-box RNA Helicases: genetics
KW  - DEAD-box RNA Helicases: metabolism
KW  - HEK293 Cells
KW  - Humans
KW  - Hydrolysis
KW  - Immunity, Innate
KW  - Mice
KW  - Models, Molecular
KW  - Molecular Sequence Data
KW  - Mutation
KW  - Protein Binding
KW  - Protein Folding
KW  - Protein Structure, Tertiary
KW  - RNA, Double-Stranded: metabolism
KW  - Signal Transduction
KW  - Simian virus 5: immunology
KW  - Sus scrofa
KW  - Viral Proteins: chemistry
KW  - Viral Proteins: genetics
KW  - Viral Proteins: metabolism
KW  - RNA, Double-Stranded (NLM Chemicals)
KW  - V protein, Paramyxovirus (NLM Chemicals)
KW  - Viral Proteins (NLM Chemicals)
KW  - Adenosine Triphosphate (NLM Chemicals)
KW  - DDX58 protein, human (NLM Chemicals)
KW  - DEAD-box RNA Helicases (NLM Chemicals)
KW  - IFIH1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:23328395
UR  - <Go to ISI:>//WOS:000314585600041
DO  - DOI:10.1126/science.1230949
UR  - https://bib-pubdb1.desy.de/record/141093
ER  -