HUMAN PEROXISOMAL TARGETING SIGNAL-1 RECEPTOR RESTORES PEROXISOMAL PROTEIN IMPORT IN CELLS FROM PATIENTS WITH FATAL PEROXISOMAL DISORDERS

Two peroxisomal targeting signals, PTS1 and PTS2, are involved in the import of proteins into the peroxisome matrix. Human patients with fat al generalized peroxisomal deficiency disorders fall into at least nin e genetic complementation groups. Cells from many of these patients ar e deficient in the import of PTS1-containing proteins, but the causes of the protein-import defect in these patients are unknown. We have cl oned and sequenced the human cDNA homologue (PTS1R) of the Pichia past oris PAS8 gene, the PTS1 receptor (McCollum, D., E, Monosov, and S. Su bramani. 1993. J. Cell Biol. 121:761-774). The PTS1R mRNA is expressed in all human tissues examined. Antibodies to the human PTS1R recogniz e this protein in human, monkey, rat, and hamster cells. The protein i s localized mainly in the cytosol but is also found to be associated w ith peroxisomes. Part of the peroxisomal PTS1R protein is tightly boun d to the peroxisomal membrane. Antibodies to PTS1R inhibit peroxisomal protein-import of PTS1-containing proteins in a permeabilized CHO cel l system. In vitro-translated PTS1R protein specifically binds a serin e-lysine-leucine-peptide. A PAS8-PTS1R fusion protein complements the P. pastoris pas8 mutant. The PTS1R cDNA also complements the PTS1 prot ein-import defect in skin fibroblasts from patients-belonging to compl ementation group two-diagnosed as having neonatal adrenoleukodystrophy or Zellweger syndrome. The PTS1R gene has been localized to a chromos omal location where no other peroxisomal disorder genes are known to m ap. Our findings represent the only case in which the molecular basis of the protein-import deficiency in human peroxisomal disorders is und erstood.