DISTINCT FUNCTIONS OF THE CLOSELY-RELATED TANDEM RNA-RECOGNITION MOTIFS OF HNRNP A1

hnRNP A1 regulates alternative splicing by antagonizing SR proteins. I t consists of two closely related, tandem RNA-recognition motifs (RRMs ), followed by a glycine-rich domain. Analysis of variant proteins wit h duplications, deletions, or swaps of the RRMs showed that although b oth RRMs ave required for alternative splicing function, each RRM play s distinct roles, and their relative position is important. Surprising ly, RRM2 but not RRM1 could support this function when duplicated, des pite their very similar structure. Specific RNA binding and annealing are not sufficient for hnRNP Al alternative splicing function. These o bservations, together with phylogenetic and structural data, suggest t hat the two RRMs are quasi-symmetric but functionally nonequivalent mo dules that evolved as components of a single bipartite domain.