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Poliovirus 3AB protein is the first picornavirus protein demonstrated to have nucleic acid chaperone activity. Further characterization of 3AB demonstrates that the C-terminal 22 amino acids (3B region (also referred to as VPg), amino acid 88-109) of the protein is required for chaperone activity, as mutations in this region abrogate nucleic acid binding and chaperone function. Protein 3B alone has no chaperone activity as determined by established assays that include the ability to stimulate nucleic acid hybridization in a primer-template annealing assay, helix-destabilization in a nucleic acid unwinding assay, or aggregation of nucleic acids. In contrast, the putative 3AB C-terminal cytoplasmic domain (C terminal amino acids 81-109, 3B + the last 7 C-terminal amino acids of 3A, termed 3B+7 in this report) possesses strong activity in these assays, albeit at much higher concentrations than 3AB. The characteristics of several mutations in 3B+7 are described here, as well as a model proposing that 3B+7 is the site of the “intrinsic” chaperone activity of 3AB while the 3A N-terminal region (amino acids 1-58) and/or membrane anchor domain (amino acids 59-80) serve to increase the effective concentration of the 3B+7 region leading to the potent chaperone activity of 3AB.