8zu6
Solution NMR Structure of PACT D3 Homodimer
Structural highlights
DiseasePRKRA_HUMAN Defects in PRKRA are the cause of dystonia type 16 (DYT16) [MIM:612067. DYT16 is an early-onset dystonia-parkinsonism disorder. Dystonia is defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT16 patients have progressive, generalized dystonia with axial muscle involvement, oro-mandibular (sardonic smile) and laryngeal dystonia and, in some cases, parkinsonian features.[1] [2] FunctionPRKRA_HUMAN Activates EIF2AK2/PKR in the absence of double stranded RNA (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition of translation and induction of apoptosis. Required for siRNA production by DICER1 and for subsequent siRNA-mediated post-transcriptional gene silencing. Does not seem to be required for processing of pre-miRNA to miRNA by DICER1.[3] [4] [5] [6] [7] [8] Publication Abstract from PubMedThe innate immune sensor PKR for double-stranded RNA (dsRNA) is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a critical yet controversial role in this pathway. We show that PACT directly suppresses PKR activation by endogenous dsRNA ligands, such as inverted-repeat Alu RNAs, which robustly activate PKR in the absence of PACT. Instead of competing for dsRNA binding, PACT prevents PKR from scanning along dsRNA-a necessary step for PKR molecules to encounter and phosphorylate each other for activation. While PKR favors longer dsRNA for increased co-occupancy and scanning-mediated activation, longer dsRNA is also more susceptible to PACT-mediated regulation due to increased PACT-PKR co-occupancy. Unlike viral inhibitors that constitutively suppress PKR, this RNA-dependent mechanism allows PACT to fine-tune PKR activation based on dsRNA length and quantity, ensuring self-tolerance without sequestering most cellular dsRNA. PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration.,Ahmad S, Zou T, Hwang J, Zhao L, Wang X, Davydenko A, Buchumenski I, Zhuang P, Fishbein AR, Capcha-Rodriguez D, Orgel A, Levanon EY, Myong S, Chou J, Meyerson M, Hur S Nat Commun. 2025 Apr 8;16(1):3325. doi: 10.1038/s41467-025-58433-x. PMID:40199855[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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