The non-structural protein NS5A is an active hepatitis C virus (HCV) replicase component, a pivotal regulator of replication, and a modulator of several cellular processes which range from innate immunity to dysregulated cell growth. NS5A is organized into three domains, labelled I, II and III. Domain I contains a zinc-binding motif and an amphipathic N-terminal helix which promotes membrane association. Mutations disrupting either the membrane anchor or zinc binding are lethal for RNA replication PMID:19244328,PMID:24639329.

Structural domains comprising this superfamily share the structure of domain 1A of the hepatitis C virus NS5A protein. This domain is involved in zinc binding and it is thought to be key for fold maintenance and is essential for replicase function PMID:15902263.