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Secretion of Peptides and Proteins Lacking Hydrophobic Signal Sequences: The Role of Adenosine Triphosphate-Driven Membrane Translocators^*

Department of Molecules Genetics, University and Biocenter Vienna A-1030 Vienna, Austria
Department of Molecular and Cell Biology, University of California Berkeley, California 94720

Correspondence: Address requests for reprints to: Karl Kuchler, Ph.D., Department of Molecular Genetics, University and Biocenter of Vienna, Dr. Bohr-Gasse 9, Vienna, A-1030, Austria. Phone:(43)-222-79515-2111, FAX:(43)-222-798-6224

Abstract

IN THIS review, we will emphasize the role of ATP-dependent membrane transporters in protein export and intracellular protein trafficking in prokaryotic and eukaryotic cells. ATP-binding-cassette (ABC)-transport proteins, also termed "traffic ATPases," belong to a superfamily of ubiquitous ATP-driven membrane transporters that share extensive sequence similarity and highly conserved domain organization. They are implicated in a remarkable variety of transmembrane transport processes, including the transport of ions, heavy metals, sugars, anticancer drugs, amino acids, oligopeptides, and proteins. Bacterial ABC-proteins include the well-characterized periplasmic permeases involved in nutrient uptake, but also include protein secretion systems, such as the exporter for the Escherichia coli enterotoxin hemolysin A. Prominent eukaryotic members of this superfamily include the human P-glycoprotein (which is associated with the phenomenon of multiple drug resistance in tumor cells), the product of the cystic fibrosis gene (CFTR), the gene (pfmdr) implicated in chloroquine resistance of the malarial parasite, putative peptide transporters encoded at the locus for the class II major histocompatibility complex (MHC), and the yeast Ste6 transporter which mediates export of a peptide hormone that lacks a classical hydrophobic signal peptide. The well-established function of prokaryotic ABC-transporters in the secretion of proteins without typical signal sequences, and the example set by the Ste6 transporter, have led to the reasonable hypothesis that certain ABC-proteins in animal cells may be operating by a similiar mechanism to mediate the export of a new class of secretory proteins, those lacking a classical hydrophobic signal peptide.

Footnotes

^* Work described in this review was supported by postdoctoral fellowships from the Max Kade Foundation, the Austrian Chamber of Commerce, the Erwin Schrödinger Foundation of the "Fonds zur Förderung der wissenschaftlichen Forschung" of the Austrian government (to K.K.), and by NIH Research Grant GM-2184 and funds provided by the Keck Foundation (to J.T.).

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