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J Biol Chem. 1994 Jun 10;269(23):16305-10.

Signal peptide cleavage regions. Functional limits on length and topological implications.

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  • 1Department of Molecular & Cell Biology, University of Connecticut, Storrs 06269.


As a first step toward understanding the topology of the signal peptide with respect to the membrane during the protein export process, we have examined the constraints on the length of the cleavage region needed to achieve signal peptidase recognition and cleavage. Using the signal peptide of Escherichia coli alkaline phosphatase, a series of cleavage region mutants has been constructed. Variations in length were brought about by replacing the wild type cleavage region of the signal peptide with polymers of increasingly more residues. In each case, alanine residues are used exclusively in the -1 and -3 positions to provide only one viable cleavage site. Glutamine residues are used in all other positions in order to vary the length from 3 to 13 total residues. Analysis of these mutants revealed that cleavage regions ranging from 3 to 9 residues are completely and efficiently processed. The extent of processing drops substantially thereafter, with no processing observed for signal peptides with 13-residue long cleavage regions. A second mutant with a 13-residue long cleavage region was designed and analyzed to ensure that the lack of processing reflected a cleavage problem and not a translocation defect. The results are consistent with the notion that the signal peptidase active site is in close proximity to the periplasmic surface of the inner membrane and that interaction of the cleavage region with the signal peptidase probably depends on, and is constrained by, other interactions involving the signal peptide.

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