Loop-mediated regulation and base flipping drive RNA cleavage by human mitochondrial PNPase.

ABSTRACT: Human polynucleotide phosphorylase (hPNPase), a trimeric exoribonuclease, is crucial for maintaining mitochondrial RNA metabolism, including the regulated degradation of RNA. Mutations in hPNPase have been linked to mitochondrial pathologies, underscoring its importance in mitochondrial RNA homeostasis. Despite this significance, the molecular basis of its catalytic mechanism and the structural consequences of active-site mutations remain poorly understood. We employed high-resolution electron cryo-microscopy to capture three distinct functional states of hPNPase during RNA degradation. In the loading state, flexible loops facilitate the recruitment of the substrate RNA and guide it toward the active site. During the pre-catalytic state, terminal nucleotides reorient within the active site

SUBMITTER: Unseld O 

PROVIDER: S-EPMC12685370 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature