In eukaryotic cells, components of the 5' to 3' mRNA degradation machinery can 
undergo a rapid phase transition. The resulting cytoplasmic foci are referred to 
as processing bodies (P-bodies). The molecular details of the self-aggregation 
process are, however, largely undetermined. Herein, we use a bottom-up approach 
that combines NMR spectroscopy, isothermal titration calorimetry, X-ray 
crystallography, and fluorescence microscopy to probe if mRNA degradation 
factors can undergo phase transitions in vitro. We show that the 
Schizosaccharomyces pombe Dcp2 mRNA decapping enzyme, its prime activator Dcp1, 
and the scaffolding proteins Edc3 and Pdc1 are sufficient to reconstitute a 
phase-separation process. Intermolecular interactions between the Edc3 LSm 
domain and at least 10 helical leucine-rich motifs in Dcp2 and Pdc1 build the 
core of the interaction network. We show that blocking of these interactions 
interferes with the clustering behavior, both in vitro and in vivo.