Here, we reveal a remarkable complexity in the unfolding of giant HEAT-repeat 
protein PR65/A, a molecular adaptor for the heterotrimeric PP2A phosphatases. 
The repeat array ruptures at multiple sites, leading to intermediate states with 
noncontiguous folded subdomains. There is a dominant sequence of unfolding, 
which reflects a nonuniform stability distribution across the repeat array and 
can be rationalized by theoretical models accounting for heterogeneous contact 
density in the folded structure. Unfolding of certain intermediates is, however, 
competitive, leading to parallel unfolding pathways. The low-stability, central 
repeats sample unfolded conformations under physiological conditions, suggesting 
how folding directs function: certain regions present rigid motifs for molecular 
recognition, whereas others have the flexibility with which to broaden the 
search area, as in the fly-casting mechanism. Partial unfolding of PR65/A also 
impacts catalysis by altering the proximity of bound catalytic subunit and 
substrate. Thus, the repeat array orchestrates the assembly and activity of 
PP2A.