The funneled energy landscape theory implies that protein structures are minimally frustrated. Yet, because of the divergent demands between folding and function, regions of frustrated patterns are present at the active site of proteins.T o understand the effects of such local frustration in dictating the energy landscape of proteins,h ere we compare the folding mechanisms of the two alternative spliced forms of aP DZ domain (PDZ2 and PDZ2as) that share an early identical sequence and structure,w hile displaying different frustration patterns.The analysis,based on the kinetic characterization of al arge number of site-directed mutants,r eveals that although the late stages for folding are very robust and biased by native topology,t he early stages are more malleable and dominated by local frustration. The results are briefly discussed in the context of the energy-landscape theory.