The tetratricopeptide repeat (TPR) is a degenerate, repeating amino acid motif of 34 residues that has been identified in a variety of proteins; however, no biochemical function has been established for it. In a two-hybrid screen for interaction with the GAP-related domain of neurofibromin, the product of the NF1 gene, we have identified two novel human genes encoding proteins with TPR motifs. The first, represented by cDNA tpr1, is located in chromosome 5q32-33.2. It is ubiquitously expressed as a 1.6-kb transcript that encodes three tandem TPR motifs, but is not related to any other known gene outside this domain. The second, defined by cDNA tpr2, maps to human chromosome 17q11.2-23. It is ubiquitously expressed as a 2.2-kb transcript encoding seven TPR units. Interestingly, a separate region of the tpr2 cDNA has striking similarity to the "J region" of the DnaJ family. The products of the tpr1 and tpr2 cDNAs interact preferentially with a truncated form of the NF1 GAP-related domain via their TPR regions, suggesting that they may be targeted to an abnormality of protein folding.