An RNA Aptamer Inhibits a Mutation-Induced Inactivating Misfolding of a Serpin.
Most serpins are fast and specific inhibitors of extracellular serine proteases controlling biological processes such as blood coagulation, fibrinolysis, tissue remodeling, and inflammation. The inhibitory activity of serpins is based on a conserved metastable structure and their conversion to a more stable state during reaction with the target protease. However, the metastable state also makes serpins vulnerable to mutations, resulting in disease caused by inactive and misfolded monomeric or polymeric forms ("serpinopathy"). Misfolding can occur either intracellularly (type-I serpinopathies) or extracellularly (type-II serpinopathies). We have isolated a 2'-fluoropyrimidine-modified RNA aptamer, which inhibits a mutation-induced inactivating misfolding of the serpin α1-antichymotrypsin. It is the first agent able to stabilize a type-II mutation of a serpin without interfering with the inhibitory mechanism, thereby presenting a solution for the long-standing challenge of preventing pathogenic misfolding without compromising the inhibitory function.
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
Jeppe B
JB
Madsen
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
Lisbeth M
LM
Andersen
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
Daniel M
DM
Dupont
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Morten B
MB
Trelle
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
Jesper S
JS
Johansen
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Jan K
JK
Jensen
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Thomas J D
TJ
Jørgensen
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark. Electronic address: pa@mbg.au.dk.
Peter A
PA
Andreasen
D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000494:pharmacology*; D041961:Deuterium Exchange Measurement; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D009154:Mutation; D017510:Protein Folding / Q000187:drug effects*; D015843:Serpins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020349:Surface Plasmon Resonance
D052157:Aptamers, Nucleotide; D015843:Serpins