hnRNP A1 regulates alternative splicing by antagonizing
SR proteins. It consists of two closely related, tandem
RNA-recognition motifs (RRMs), followed by a glycine-rich
domain. Analysis of variant proteins with duplications,
deletions, or swaps of the RRMs showed that although both
RRMs are required for alternative splicing function, each
RRM plays distinct roles, and their relative position is
important. Surprisingly, RRM2 but not RRM1 could support
this function when duplicated, despite their very similar
structure. Specific RNA binding and annealing are not sufficient
for hnRNP A1 alternative splicing function. These observations,
together with phylogenetic and structural data, suggest
that the two RRMs are quasi-symmetric but functionally
nonequivalent modules that evolved as components of a single
bipartite domain.