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Structural and hydrodynamic characterization of dimeric human oligoadenylate synthetase 2

DOI: 10.1016/j.bpj.2020.04.025 DOI Help

Authors: Amit Koul (University of Manitoba) , Darren Gemmill (University of Lethbridge) , Nikhat Lubna (University of Manitoba) , Markus Meier (University of Manitoba) , Natalie Krahn (Yale University) , Evan P. Booy (University of Manitoba) , Jörg Stetefeld (University of Manitoba) , Trushar R. Patel (University of Lethbridge; University of Calgary; University of Alberta) , Sean A. Mckenna (University of Manitoba)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biophysical Journal

State: Published (Approved)
Published: May 2020
Diamond Proposal Number(s): 16028 , 22113

Open Access Open Access

Abstract: Oligoadenylate synthetases (OASs) are a family of interferon-inducible enzymes that require double-stranded RNA (dsRNA) as a cofactor. Upon binding dsRNA, OAS undergoes a conformational change and is activated to polymerize ATP into 2′-5′-oligoadenylate chains. The OAS family consists of several isozymes, with unique domain organizations to potentially interact with dsRNA of variable length, providing diversity in viral RNA recognition. In addition, oligomerization of OAS isozymes, potentially OAS1 and OAS2, is hypothesized to be important for 2′-5′-oligoadenylate chain building. In this study, we present the solution conformation of dimeric human OAS2 using an integrated approach involving small-angle x-ray scattering, analytical ultracentrifugation, and dynamic light scattering techniques. We also demonstrate OAS2 dimerization using immunoprecipitation approaches in human cells. Whereas mutation of a key active-site aspartic acid residue prevents OAS2 activity, a C-terminal mutation previously hypothesized to disrupt OAS self-association had only a minor effect on OAS2 activity. Finally, we also present the solution structure of OAS1 monomer and dimer, comparing their hydrodynamic properties with OAS2. In summary, our work presents the first, to our knowledge, dimeric structural models of OAS2 that enhance our understanding of the oligomerization and catalytic function of OAS enzymes.

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: B21-High Throughput SAXS

Added On: 21/05/2020 13:30


Discipline Tags:

Biochemistry Catalysis Chemistry Structural biology Biophysics Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)