An intrinsically disordered region controls viperin (SAND) antiviral synthesis via a clamp-and-latch mechanism

Abstract

Inter-individual susceptibility to viral infections is a public health challenge. Understanding the structure and function of antiviral restriction-factor enzymes is necessary to link genetic variants to viral susceptibility. Viperin (SAND) is a sentinel antiviral restriction factor with broad-spectrum activity believed to preferentially select cytidine triphosphate (CTP) based on the structure of the active site. Here, we studied fungal, rat, and human SANDs. We found that a C-terminal intrinsically disordered region (IDR) ensemble, not the active site, is the key structural element enabling the enzyme to select multiple ribonucleoside triphosphates (rNTPs). We demonstrate that the IDR ensemble functions via a clamp-and-latch mechanism that depends on the IDR-adjacent folded domain (context). Consequently, human and rat enzymes with different contexts have different catalytic outputs. These findings revise our understanding of viperin catalytic function and identify an IDR-dependent element in the evolution of antiviral defense.