The PR65/A subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit, generating functionally diverse heterotrimers. Mutations of the β isoform of PR65 are associated with lung and colon tumors. The crystal structure of the PR65/A α subunit, at 2.3 Å resolution, reveals the conformation of its 15 tandemly repeated HEAT sequences, degenerate motifs of ∼39 amino acids present in a variety of proteins, including huntingtin and importin β. Individual motifs are composed of a pair of antiparallel α helices that assemble in a mainly linear, repetitive fashion to form an elongated molecule characterized by a double layer of α helices. Left-handed rotations at three interrepeat interfaces generate a novel left-hand superhelical conformation. The protein interaction interface is formed from the intrarepeat turns that are aligned to form a continuous ridge.