Functional RNA structures throughout the Hepatitis C Virus genome

Abstract

The single-stranded Hepatitis C Virus (HCV) genome adopts a set of elaborate RNA structures that are involved in every stage of the viral lifecycle. Recent advances in chemical probing, sequencing, and structural biology have facilitated analysis of RNA folding on a genome-wide scale, revealing novel structures and networks of interactions. These studies have underscored the active role played by RNA in every function of HCV and they open the door to new types of RNA-targeted therapeutics.

Figure 1

Secondary, tertiary, and quaternary structural elements of the HCV genome. Labels at bottom indicate region of the genome where structures are located. A. Structures within the positive-sense strand of HCV genome. Long-range tertiary interactions are depicted in dark grey. Alternate stem-loop and clover-leaf structures of SL6038 depicted. B. Negative-sense strand 3′ end of HCV genome [49,50].

Figure 2

Structural features of the HCV IRES. A. 2D structure of the HCV IRES. Domains of the IRES are color-coded according to the legend. B. IRES-40S interaction. Binary interaction between the IRES and human 40S ribosomal subunit. Adapted from [6], PDB 5A2Q. C. Benzimidazole straightens the bend in domain II. Structure of the bend region of domain II (domain IIa) complexed with 40S (left) and the corresponding region complexed with benzimidazole (right). Right adapted from [33], PDB 3TZR.

Figure 3

Base-pairing interactions between the HCV 5′ UTR and miR-122. Two copies of miR-122 bind the 5′ end of the HCV genome via canonical seed-sequence interactions (purple) and additional interactions (red). The unpaired 3′ ends of miR-122 are depicted, as well as bulges formed in miR-122 and SLI/domain I of HCV. Adapted from [13].

Figure 4

Structure of the Flavivirus sfRNA from Zika Virus. A. 2D structure of Zika sfRNA with stem-loops color-coded and pseudoknot depicted. B. Crystal structure of Zika sfRNA. Shown in orange and blue, the 3′ end of the first stem-loop wraps around the 5′ end of the RNA, inhibiting unwinding from the 5′ end. Adapted from [43], PDB 5TPY.