Human PUMILIO1 (PUM1) and PUMILIO2 (PUM2) are members of the PUMILIO/FBF (PUF) 
family that regulate specific target mRNAs posttranscriptionally. Recent studies 
have identified mRNA targets associated with human PUM1 and PUM2. Here, we 
explore the structural basis of natural target RNA recognition by human PUF 
proteins through crystal structures of the RNA-binding domains of PUM1 and PUM2 
in complex with four cognate RNA sequences, including sequences from p38α and 
erk2 MAP kinase mRNAs. We observe three distinct modes of RNA binding around the 
fifth RNA base, two of which are different from the prototypical 1 repeat:1 RNA 
base binding mode previously identified with model RNA sequences. RNA-binding 
affinities of PUM1 and PUM2 are not affected dramatically by the different 
binding modes in vitro. However, these modes of binding create structurally 
variable recognition surfaces that suggest a mechanism in vivo for recruitment 
of downstream effector proteins defined by the PUF:RNA complex.