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Structural features in the amino terminal region of a model eukaryotic signal peptide influence the site of its cleavage by signal peptidase


Structural features in the amino terminal region of a model eukaryotic signal peptide influence the site of its cleavage by signal peptidase



Journal of Biological Chemistry 265(28): 17202-17208



ISSN/ISBN: 0021-9258

The 20-amino acid signal peptide of human pre (.DELTA.pro)apolipoprotein A-II contains the tripartite domain structure typical of eukaryotic prepetides, i.e. a positively charged NH2-terminal (n) region, a hydrophobic core (h) region, and a COOH-terminal polar domain (c region). This signal sequence has multiple potential sites for cotranslational processing making it an attractive model for assessing the consequences of systematic structural alterations on the site selected for signal peptidase cleavage. We previously analyzed 40 mutant derivatives of this model preprotein using an in vitro translation/canine microsome processing assay. The results showed that the position of the boundary between the h and c regions and properties of the -1 residue are critical in defining the site of cotranslational cleavage. To investigate whether structural features in the NH2-terminal region of signal peptides play a role in cleavage specificity, we have now inserted various amino acids between the positively charged n region (NH2-Met-Lys) and the h region of a "parental" pre(.DELTA.pro)apoA-II mutant that has roughly equal cleavage between Gly18.dwnarw. and Gly20.dwnarw. Movement of the n/h boundary toward the NH2 terminus results in a dramatic shift in cleavage to Gly18.dwnarw. Replacement of the Lys2 residue with hydrophilic, negatively charged residues preserves the original sites of cleavage. Replacement with a hydrophobic residue causes cleavage to shift "upstream". Simultaneous alteration of the position of n/h and h/c boundaries has an additive effect on the site of signal peptidase cleavage. None of these mutations produced a marked decrease in the efficiency of in vitro cotranslational translocationor cleavage. However, in sequence contexts having poor signal function, introduction of hydrophobic residues between the n and h regions markedly improved the efficiency of translocation/processing. We conclude that the position of the n/h boundary as well as positioning of the h/c boundary affects the site of cleavage chosen by signal peptidase.

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Accession: 007825057

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Related references

Structural features in teh NH2-terminal region of a model eukaryotic signal peptide influence the site of its cleavage by signal peptidase. The Journal of Biological Chemistry 265(28): 17202-17208, 1990

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