Mechanism of OAS1 Activation by a Conserved SARS-CoV-2 Region Restricted; Files Only

Abstract

The first line of cellular defense against pathogens is the innate immune system, which is composed of different pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). Cytosolic double-stranded RNA (dsRNA), for example, is a PAMP that is particularly indicative of viral infection. Recognition of dsRNA by the PRR 2’,5’- oligoadenylate synthetase 1 (OAS1) allosterically induces changes in the enzyme active site to promote 2’,5’-oligoadenylate synthesis, culminating in activation of the OAS/RNase L pathway and blockade of viral replication. A reduction in disease severity of Covid-19 has been found to be associated with an isoform of OAS1, whose production is attributed to a single nucleotide polymorphism (SNP) that causes alternative splicing and thus the expression of OAS1-p46, rather than the typical OAS1-p42. The p46 isoform contains a sequence for prenylation (lipid modification) at its C-terminus, allowing it to be membrane-anchored, and thereby enabling recognition of dsRNA structures within the 5’ UTR of SARS-CoV-2 in the viral replication organelle. The overall goal of my research is to define the 5’ region of the SARS-CoV-2 genome that can bind to and activate OAS1, and to probe key features of this RNA domain to uncover its mechanism of activation of OAS1. 

Table of Contents

Table of Contents

Introduction 1

Figure 1. The OAS/RNase L Pathway shown for OAS1. 2

Methods and Results 5

Figure 2. Overview of the Experimental Procedures used in this Study. 5

Figure 3. Structural and Biochemical Analysis of 3’-End Truncations. 7

Figure 4. OAS1 Activation by RNA Constructs. 9

Discussion 10

Figure 5. Model of OAS1-p46 binding SL4. 11

References 13

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Biochemistry
Keyword	SARS-CoV-2 OAS1 RNA
Committee Chair / Thesis Advisor	Graeme Conn, PhD, Emory University
Committee Members	Cora MacBeth, PhD, Emory University Jose Soria, PhD, Emory University

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