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J Biol Chem, Vol. 274, Issue 53, 37750-37754, December 31, 1999

Signal Peptides Having Standard and Nonstandard Cleavage Sites Can Be Processed by Imp1p of the Mitochondrial Inner Membrane Protease^*

Xuemin Chen, Clint Van Valkenburgh, Hong Fang, and Neil Green

From the Department of Microbiology and Immunology, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232-2363

We have performed a site-directed mutagenesis study showing that residues comprising the type I signal peptidase signature in the two catalytic subunits of the yeast inner membrane protease, Imp1p and Imp2p, are functionally important, consistent with the idea that these subunits contain a serine/lysine catalytic dyad. Previous studies have shown that Imp1p cleaves signal peptides having asparagine at the 1 position, which deviates from the typical signal peptide possessing a small uncharged amino acid at this position. To determine whether asparagine is responsible for the nonoverlapping substrate specificities exhibited by the inner membrane protease subunits, we have substituted asparagine with 19 amino acids in the Imp1p substrate i-cytochrome (cyt) b₂. The resulting signal peptides containing alanine, serine, cysteine, leucine, and methionine can be cleaved efficiently by Imp1p. The remaining mutant signal peptides are cleaved inefficiently or not at all. Surprisingly, none of the amino acid changes results in the recognition of i-cyt b₂ by Imp2p, whose natural substrate, i-cyt c₁, has alanine at the 1 position. The data demonstrate that (i) although the 1 residue is important in substrates recognized by Imp1p, signal peptides having standard and nonstandard cleavage sites can be processed by Imp1p, and (ii) a 1 asparagine does not govern the substrate specificity of the inner membrane protease subunits.

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^* This work was supported by Department of Health and Human Services Training Grant 2 T32 CA09385-11 (to C. V.) and by grants from the National Science Foundation (to H. F. and N. G.) and American Heart Association (to N. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 615-343-0453; Fax: 615-343-7392; E-mail: neil.green@mcmail.vanderbilt.edu.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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