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Here, we reveal that in Protein Kinase R (PKR)\u2014an RBP that triggers the innate immune response upon sensing double-stranded RNAs (dsRNAs)\u2014its two dsRNA-binding domains (dsRBDs) assemble into a unique architecture through intramolecular interactions. This dsRBD1:dsRBD2 interface allows PKR to convert diffusive, transient contacts with RNA into a stabilized complex on the duplex, establishing a scaffold required for downstream protein dimerization and phosphorylation. Disrupting this dsRBD1:dsRBD2 interface dismantles the tandem dsRBD architecture and severely impairs PKR activity both in vitro and in cells. Together, these findings uncover an exceptional advantage of the tandem dsRBD arrangement and underscore intramolecular RBD coupling as a mechanism for regulating RBP activity.<\/jats:p>","DOI":"10.1073\/pnas.2605220123","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T16:13:32Z","timestamp":1790784812000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Tandem RNA-binding domain architecture drives PKR activation through an intramolecular interface"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8125-4090","authenticated-orcid":false,"given":"Chong","family":"Han","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Key Laboratory of Molecular Andrology, Center for Excellence in Molecular Cell 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