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J. Biol. Chem., Vol. 280, Issue 22, 21176-21182, June 3, 2005

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Function of the PEX19-binding Site of Human Adrenoleukodystrophy Protein as Targeting Motif in Man and Yeast

PMP TARGETING IS EVOLUTIONARILY CONSERVED^*

André Halbach, Stephan Lorenzen¶, Christiane Landgraf||, Rudolf Volkmer-Engert||, Ralf Erdmann**, and Hanspeter Rottensteiner

From the Institut für Physiologische Chemie, Abteilung Systembiochemie, Ruhr-Universität Bochum, 44780 Bochum, Germany, ^¶Institut für Biochemie and ^||Institut für Medizinische Immunologie, Universitätsklinikum Charité, 10115 Berlin, Germany

We predicted in human peroxisomal membrane proteins (PMPs) the binding sites for PEX19, a key player in the topogenesis of PMPs, by virtue of an algorithm developed for yeast PMPs. The best scoring PEX19-binding site was found in the adrenoleukodystrophy protein (ALDP). The identified site was indeed bound by human PEX19 and was also recognized by the orthologous yeast PEX19 protein. Likewise, both human and yeast PEX19 bound with comparable affinities to the PEX19-binding site of the yeast PMP Pex13p. Interestingly, the identified PEX19-binding site of ALDP coincided with its previously determined targeting motif. We corroborated the requirement of the ALDP PEX19-binding site for peroxisomal targeting in human fibroblasts and showed that the minimal ALDP fragment targets correctly also in yeast, again in a PEX19-binding site-dependent manner. Furthermore, the human PEX19-binding site of ALDP proved interchangeable with that of yeast Pex13p in an in vivo targeting assay. Finally, we showed in vitro that most of the predicted binding sequences of human PMPs represent true binding sites for human PEX19, indicating that human PMPs harbor common PEX19-binding sites that do resemble those of yeast. Our data clearly revealed a role for PEX19-binding sites as PMP-targeting motifs across species, thereby demonstrating the evolutionary conservation of PMP signal sequences from yeast to man.

Received for publication, February 15, 2005 , and in revised form, March 16, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB480 (to H. R.), SFB449 (to R. V.-E.), and SFB1992 (to R. E.), and by the FP6 European Union Project "Peroxisome" (LSHG-CT-2004-512018), and by the Fonds der Chemischen Industrie. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 234-322-4943; Fax: 234-321-4266; E-mail: Ralf.Erdmann{at}rub.de.

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