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It is comprised of a folded nucleic acid binding domain (NTD) and a dimerization domain, connected by a disordered linker containing a serine\/arginine-rich (SR) region and a leucine-rich sequence (LRS). The switch between intracellular and assembly functions of N-protein is controlled by phosphorylation of the SR region, but the molecular details are unclear. Here we describe a model in which two mutually exclusive intramolecular loops bind the NTD and dynamically control self-association and nucleic acid binding properties dependent on the SR linker phosphorylation state. The model is supported by biophysical properties and interactions of full-length protein, point mutants, and peptide fragments. We find SR linker phosphorylation compacts the protein and inhibits nucleic acid binding and RNP formation, while enhancing self-association through promotion of transient coiled-coils in the LRS of the linker. These changes shift the nucleocapsid protein to a configuration poised for multi-valent interactions that support intracellular functions.<\/jats:p>","DOI":"10.64898\/2026.01.10.698783","type":"posted-content","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T03:50:11Z","timestamp":1768276211000},"source":"Crossref","is-referenced-by-count":0,"title":["Intramolecular loops control SARS-CoV-2 nucleocapsid protein self-association and nucleic acid binding dependent on phosphorylation"],"prefix":"10.64898","author":[{"given":"Ai","family":"Nguyen","sequence":"first","affiliation":[{"name":"Laboratory of Dynamics of Macromolecular Assembly, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddhartha A.K.","family":"Datta","sequence":"additional","affiliation":[{"name":"Laboratory of Dynamics of Macromolecular Assembly, National Institute of 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