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• W1984429232 abstract "The yeast mating pheromone a-factor precursor contains an N-terminal extension and a C-terminal CAAX motif within which multiple posttranslational processing events occur. A recently discovered component in a-factor processing is Ste24p/Afc1p, a multispanning endoplasmic reticulum membrane protein that contains an HEXXH metalloprotease motif. Our in vivo genetic characterization of this protein has demonstrated roles for Ste24p in both the N-terminal and C-terminal proteolytic processing of the a-factor precursor. Here, we present evidence that the N-terminal proteolysis of the a-factor precursor P1 can be accurately reconstituted in vitro using yeast membranes. We show that this activity is dependent on Ste24p and is abolished by mutation of the Ste24p HEXXH metalloprotease motif or by mutation of the a-factor P1 substrate at a residue adjacent to the N-terminal P1 cleavage site. We also demonstrate that N-terminal proteolysis of the P1 a-factor precursor requires Zn2+ as a co-factor and can be inhibited by the addition of the metalloprotease inhibitor 1,10-orthophenanthroline. Our results are consistent with Ste24p itself being the P1→P2 a-factor protease or a limiting activator of this activity. Interestingly, we also show that the humanSte24 homolog expressed in yeast can efficiently promote the N-terminal processing of a-factor in vivo and in vitro, thus establishing a-factor as a surrogate substrate in the absence of known human substrates. The results reported here, together with the previously reported in vitro reconstitution of Ste24p-dependent CAAX processing, provide a system for examining the potential bifunctional roles of yeast Ste24p and its homologs. The yeast mating pheromone a-factor precursor contains an N-terminal extension and a C-terminal CAAX motif within which multiple posttranslational processing events occur. A recently discovered component in a-factor processing is Ste24p/Afc1p, a multispanning endoplasmic reticulum membrane protein that contains an HEXXH metalloprotease motif. Our in vivo genetic characterization of this protein has demonstrated roles for Ste24p in both the N-terminal and C-terminal proteolytic processing of the a-factor precursor. Here, we present evidence that the N-terminal proteolysis of the a-factor precursor P1 can be accurately reconstituted in vitro using yeast membranes. We show that this activity is dependent on Ste24p and is abolished by mutation of the Ste24p HEXXH metalloprotease motif or by mutation of the a-factor P1 substrate at a residue adjacent to the N-terminal P1 cleavage site. We also demonstrate that N-terminal proteolysis of the P1 a-factor precursor requires Zn2+ as a co-factor and can be inhibited by the addition of the metalloprotease inhibitor 1,10-orthophenanthroline. Our results are consistent with Ste24p itself being the P1→P2 a-factor protease or a limiting activator of this activity. Interestingly, we also show that the humanSte24 homolog expressed in yeast can efficiently promote the N-terminal processing of a-factor in vivo and in vitro, thus establishing a-factor as a surrogate substrate in the absence of known human substrates. The results reported here, together with the previously reported in vitro reconstitution of Ste24p-dependent CAAX processing, provide a system for examining the potential bifunctional roles of yeast Ste24p and its homologs. endoplasmic reticulum Precursors of the S. cerevisiae mating pheromones, α-factor and a-factor, undergo posttranslational processing (1.Bender A. Sprague Jr., G.F. Cell. 1986; 47: 929-937Abstract Full Text PDF PubMed Scopus (65) Google Scholar, 2.Fuller R. Brake A. Sterne R. Kunisawa R. Barnes D. Flessel M. Thorner J. Hicks J. Yeast Cell Biology. Alan R. Liss, New York1986: 461-476Google Scholar, 3.Michaelis S. Chen P. Berkower C. Sapperstein S. Kistler A. Antonie Van Leeuwenhoek. 1992; 61: 115-117Crossref PubMed Scopus (11) Google Scholar). Surprisingly, the yeast mating pheromones do not share a common biosynthetic pathway even though the mature pheromones perform similar functions as secreted signaling molecules that stimulate cognate G-protein coupled receptors. The processing and export of α-factor involves translocation of its precursor into the endoplasmic reticulum (ER)1and subsequent transport of the precursor through the lumenal compartments of the classical secretory pathway, during which it is modified by resident processing enzymes of the ER, Golgi, andtrans-Golgi network (4.Julius D. Schekman R. Thorner J. Cell. 1984; 36: 309-318Abstract Full Text PDF PubMed Scopus (250) Google Scholar). In contrast, the processing of thea-factor precursor appears to occur on the cytosolic face of the ER (and possibly other intracellular membranes), yielding a cytosolically disposed mature pheromone (5.Schmidt W.K. Tam A. Fujimura-Kamada K. Michaelis S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 11175-11180Crossref PubMed Scopus (162) Google Scholar). The eventual export of the mature a-factor pheromone across the plasma membrane is accomplished by Ste6p, a dedicated transporter that is a member of the ATP-binding cassette superfamily of transporters (3.Michaelis S. Chen P. Berkower C. Sapperstein S. Kistler A. Antonie Van Leeuwenhoek. 1992; 61: 115-117Crossref PubMed Scopus (11) Google Scholar, 6.Kuchler K. Sterne R.E. Thorner J. EMBO J. 1989; 8: 3973-3984Crossref PubMed Scopus (323) Google Scholar, 7.McGrath J.P. Varshavsky A. Nature. 1989; 340: 400-404Crossref PubMed Scopus (448) Google Scholar).The S. cerevisiae a-factor mating pheromone, redundantly encoded by the MFA1 and MFA2 genes, is initially synthesized as a primary precursor (P0) that contains an N-terminal extension and a C-terminal CAAX motif (C = cysteine, A = an aliphatic amino acid, andX = one of several amino acids) (Fig.1 A). The ultimate formation of mature a-factor (M) requires multiple modifications at both ends of the primary precursor (Fig. 1 B). The first set of modifications (isoprenylation, proteolytic removal of theAAX tripeptide, and carboxylmethylation) are directed by the C-terminal CAAX motif (8.Clarke S. Annu. Rev. Biochem. 1992; 61: 355-386Crossref PubMed Scopus (788) Google Scholar, 9.Zhang F.L. Casey P.J. Annu. Rev. Biochem. 1996; 65: 241-269Crossref PubMed Scopus (1725) Google Scholar). These C-terminal modifications are common to all proteins bearing a CAAX sequence (e.g. Ras, Gγ, and nuclear lamin precursors). Fora-factor, this processing yields an intermediatea-factor species (P1) that lacks the terminal three amino acids (VIA) and has a farnesylated and carboxylmethylated C-terminal cysteine. The P1 intermediate is then trimmed of its N-terminal extension in two sequential proteolytic steps, yielding first the P2 intermediate and finally mature a-factor (M) (3.Michaelis S. Chen P. Berkower C. Sapperstein S. Kistler A. Antonie Van Leeuwenhoek. 1992; 61: 115-117Crossref PubMed Scopus (11) Google Scholar, 10.Chen P. Sapperstein S. Choi J.D. Michaelis S. J. Cell Biol. 1997; 136: 251-269Crossref PubMed Scopus (105) Google Scholar, 11.Fujimura-Kamada K. Nouvet F.J. Michaelis S. J. Cell Biol. 1997; 136: 271-285Crossref PubMed Scopus (129) Google Scholar). The initial N-terminal cleavage step (P1→P2) occurs between residues 7 (Thr) and 8 (Ala) of the a-factor precursor, and a subsequent cleavage step (P2→M) occurs between residues 21 (Asn) and 22 (Tyr) that removes the remainder of the extension. Thus, three distinct proteolytic processing events, one C-terminal and two N-terminal, are involved in a-factor maturation.Recent genetic studies have identified several components involved in the proteolytic processing of a-factor (Fig. 1 B). These include the Ste24p (also called Afc1p) and Rce1p proteins that are required for the C-terminal CAAX processing ofa-factor and other proteins bearing a CAAX motif (12.Boyartchuk V.L. Ashby M.N. Rine J. Science. 1997; 275: 1796-1800Crossref PubMed Scopus (304) Google Scholar). Ste24p and Rce1p appear to be partially redundant for this function (12.Boyartchuk V.L. Ashby M.N. Rine J. Science. 1997; 275: 1796-1800Crossref PubMed Scopus (304) Google Scholar, 13.Tam A. Nouvet F. Fujimura-Kamada K. Slunt H. Sisodia S.S. Michaelis S. J. Cell Biol. 1998; 142: 635-649Crossref PubMed Scopus (109) Google Scholar). An unanticipated finding was that Ste24p has a second distinct role in a-factor processing; namely, it also is required for the first N-terminal cleavage (P1→P2) event ofa-factor biogenesis (11.Fujimura-Kamada K. Nouvet F.J. Michaelis S. J. Cell Biol. 1997; 136: 271-285Crossref PubMed Scopus (129) Google Scholar). The dual roles of Ste24p in promoting N- and C-terminal processing are notable given that these cleavage sites are spatially separated and have little sequence similarity (Fig. 1 A). Finally, the Axl1p and Ste23p proteins were shown to have some partial overlapping function for the final N-terminal cleavage event (P2→M) that yields maturea-factor (14.Adames N. Blundell K. Ashby M.N. Boone C. Science. 1995; 270: 464-467Crossref PubMed Scopus (122) Google Scholar).Further analysis of the a-factor proteolytic processing components revealed that Ste24p and Rce1p are ER-localized membrane spanning proteins (5.Schmidt W.K. Tam A. Fujimura-Kamada K. Michaelis S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 11175-11180Crossref PubMed Scopus (162) Google Scholar). The localization of Axl1p and Ste23p has not been reported. Additionally, Ste24p, Axl1p, and Ste23p, but not Rce1p, possess consensus metalloprotease motifs that are conserved among many zinc-dependent metalloproteases (e.g.HEXXH or HXXEH). Not surprisingly, point mutations of the Ste24p metalloprotease motif (HEXXH) resulted in defective CAAX and N-terminal processing ofa-factor precursors (11.Fujimura-Kamada K. Nouvet F.J. Michaelis S. J. Cell Biol. 1997; 136: 271-285Crossref PubMed Scopus (129) Google Scholar, 12.Boyartchuk V.L. Ashby M.N. Rine J. Science. 1997; 275: 1796-1800Crossref PubMed Scopus (304) Google Scholar). Thus, the components genetically identified as being required for the proteolytic processing of a-factor may act directly on a-factor precursors as proteases, or alternatively could activate as yet unidentified downstream acting proteases. The CAAXproteolytic activities dependent on Ste24p and Rce1p were recently reconstituted in vitro using crude yeast membranes (12.Boyartchuk V.L. Ashby M.N. Rine J. Science. 1997; 275: 1796-1800Crossref PubMed Scopus (304) Google Scholar). Whereas membranes containing either Ste24p or Rce1p promoted the CAAX proteolysis of a particular farnesylated peptide substrate, only Rce1p-containing membranes could promote the CAAX proteolysis of yeast Ras2p. The Ste24p-dependent N-terminal proteolytic activity was not examined in this study.In addition to its role in CAAX proteolysis, Ste24p is likely to act directly or indirectly as a protease in the first N-terminal cleavage of the a-factor precursor, but this has not yet been examined by direct in vitro studies (11.Fujimura-Kamada K. Nouvet F.J. Michaelis S. J. Cell Biol. 1997; 136: 271-285Crossref PubMed Scopus (129) Google Scholar). Accordingly, the aim of this study was to reconstitute an in vitro system that could be used to examine the role of Ste24p in the N-terminal processing (P1→P2) of a-factor. This would enable us to gain further insight into the role of Ste24p and to initiate a characterization of the biochemical properties of the N-terminal processing activity. Here, we have faithfully reconstitutedin vitro the N-terminal proteolysis of the P1a-factor precursor using yeast membranes as the source of Ste24p and the P1 a-factor precursor. We demonstrate biochemically that this activity requires Ste24p and a metal co-factor and that the cleavage event displays substrate specificity. Finally, we show in vivo and in vitro that the human homolog of Ste24p can properly direct the N-terminal processing of the yeasta-factor precursor. Precursors of the S. cerevisiae mating pheromones, α-factor and a-factor, undergo posttranslational processing (1.Bender A. Sprague Jr., G.F. Cell. 1986; 47: 929-937Abstract Full Text PDF PubMed Scopus (65) Google Scholar, 2.Fuller R. Brake A. Sterne R. Kunisawa R. Barnes D. Flessel M. Thorner J. Hicks J. Yeast Cell Biology. Alan R. Liss, New York1986: 461-476Google Scholar, 3.Michaelis S. Chen P. Berkower C. Sapperstein S. Kistler A. Antonie Van Leeuwenhoek. 1992; 61: 115-117Crossref PubMed Scopus (11) Google Scholar). Surprisingly, the yeast mating pheromones do not share a common biosynthetic pathway even though the mature pheromones perform similar functions as secreted signaling molecules that stimulate cognate G-protein coupled receptors. The processing and export of α-factor involves translocation of its precursor into the endoplasmic reticulum (ER)1and subsequent transport of the precursor through the lumenal compartments of the classical secretory pathway, during which it is modified by resident processing enzymes of the ER, Golgi, andtrans-Golgi network (4.Julius D. Schekman R. Thorner J. Cell. 1984; 36: 309-318Abstract Full Text PDF PubMed Scopus (250) Google Scholar). In contrast, the processing of thea-factor precursor appears to occur on the cytosolic face of the ER (and possibly other intracellular membranes), yielding a cytosolically disposed mature pheromone (5.Schmidt W.K. Tam A. Fujimura-Kamada K. Michaelis S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 11175-11180Crossref PubMed Scopus (162) Google Scholar). The eventual export of the mature a-factor pheromone across the plasma membrane is accomplished by Ste6p, a dedicated transporter that is a member of the ATP-binding cassette superfamily of transporters (3.Michaelis S. Chen P. Berkower C. Sapperstein S. Kistler A. Antonie Van Leeuwenhoek. 1992; 61: 115-117Crossref PubMed Scopus (11) Google Scholar, 6.Kuchler K. Sterne R.E. Thorner J. EMBO J. 1989; 8: 3973-3984Crossref PubMed Scopus (323) Google Scholar, 7.McGrath J.P. Varshavsky A. Nature. 1989; 340: 400-404Crossref PubMed Scopus (448) Google Scholar). The S. cerevisiae a-factor mating pheromone, redundantly encoded by the MFA1 and MFA2 genes, is initially synthesized as a primary precursor (P0) that contains an N-terminal extension and a C-terminal CAAX motif (C = cysteine, A = an aliphatic amino acid, andX = one of several amino acids) (Fig.1 A). The ultimate formation of mature a-factor (M) requires multiple modifications at both ends of the primary precursor (Fig. 1 B). The first set of modifications (isoprenylation, proteolytic removal of theAAX tripeptide, and carboxylmethylation) are directed by the C-terminal CAAX motif (8.Clarke S. Annu. Rev. Biochem. 1992; 61: 355-386Crossref PubMed Scopus (788) Google Scholar, 9.Zhang F.L. Casey P.J. Annu. Rev. Biochem. 1996; 65: 241-269Crossref PubMed Scopus (1725) Google Scholar). These C-terminal modifications are common to all proteins bearing a CAAX sequence (e.g. Ras, Gγ, and nuclear lamin precursors). Fora-factor, this processing yields an intermediatea-factor species (P1) that lacks the terminal three amino acids (VIA) and has a farnesylated and carboxylmethylated C-terminal cysteine. The P1 intermediate is then trimmed of its N-terminal extension in two sequential proteolytic steps, yielding first the P2 intermediate and finally mature a-factor (M) (3.Michaelis S. Chen P. Berkower C. Sapperstein S. Kistler A. Antonie Van Leeuwenhoek. 1992; 61: 115-117Crossref PubMed Scopus (11) Google Scholar, 10.Chen P. Sapperstein S. Choi J.D. Michaelis S. J. Cell Biol. 1997; 136: 251-269Crossref PubMed Scopus (105) Google Scholar, 11.Fujimura-Kamada K. Nouvet F.J. Michaelis S. J. Cell Biol. 1997; 136: 271-285Crossref PubMed Scopus (129) Google Scholar). The initial N-terminal cleavage step (P1→P2) occurs between residues 7 (Thr) and 8 (Ala) of the a-factor precursor, and a subsequent cleavage step (P2→M) occurs between residues 21 (Asn) and 22 (Tyr) that removes the remainder of the extension. Thus, three distinct proteolytic processing events, one C-terminal and two N-terminal, are involved in a-factor maturation. Recent genetic studies have identified several components involved in the proteolytic processing of a-factor (Fig. 1 B). These include the Ste24p (also called Afc1p) and Rce1p proteins that are required for the C-terminal CAAX processing ofa-factor and other proteins bearing a CAAX motif (12.Boyartchuk V.L. Ashby M.N. Rine J. Science. 1997; 275: 1796-1800Crossref PubMed Scopus (304) Google Scholar). Ste24p and Rce1p appear to be partially redundant for this function (12.Boyartchuk V.L. Ashby M.N. Rine J. Science. 1997; 275: 1796-1800Crossref PubMed Scopus (304) Google Scholar, 13.Tam A. Nouvet F. Fujimura-Kamada K. Slunt H. Sisodia S.S. Michaelis S. J. Cell Biol. 1998; 142: 635-649Crossref PubMed Scopus (109) Google Scholar). An unanticipated finding was that Ste24p has a second distinct role in a-factor processing; namely, it also is required for the first N-terminal cleavage (P1→P2) event ofa-factor biogenesis (11.Fujimura-Kamada K. Nouvet F.J. Michaelis S. J. Cell Biol. 1997; 136: 271-285Crossref PubMed Scopus (129) Google Scholar). The dual roles of Ste24p in promoting N- and C-terminal processing are notable given that these cleavage sites are spatially separated and have little sequence similarity (Fig. 1 A). Finally, the Axl1p and Ste23p proteins were shown to have some partial overlapping function for the final N-terminal cleavage event (P2→M) that yields maturea-factor (14.Adames N. Blundell K. Ashby M.N. Boone C. Science. 1995; 270: 464-467Crossref PubMed Scopus (122) Google Scholar). Further analysis of the a-factor proteolytic processing components revealed that Ste24p and Rce1p are ER-localized membrane spanning proteins (5.Schmidt W.K. Tam A. Fujimura-Kamada K. Michaelis S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 11175-11180Crossref PubMed Scopus (162) Google Scholar). The localization of Axl1p and Ste23p has not been reported. Additionally, Ste24p, Axl1p, and Ste23p, but not Rce1p, possess consensus metalloprotease motifs that are conserved among many zinc-dependent metalloproteases (e.g.HEXXH or HXXEH). Not surprisingly, point mutations of the Ste24p metalloprotease motif (HEXXH) resulted in defective CAAX and N-terminal processing ofa-factor precursors (11.Fujimura-Kamada K. Nouvet F.J. Michaelis S. J. Cell Biol. 1997; 136: 271-285Crossref PubMed Scopus (129) Google Scholar, 12.Boyartchuk V.L. Ashby M.N. Rine J. Science. 1997; 275: 1796-1800Crossref PubMed Scopus (304) Google Scholar). Thus, the components genetically identified as being required for the proteolytic processing of a-factor may act directly on a-factor precursors as proteases, or alternatively could activate as yet unidentified downstream acting proteases. The CAAXproteolytic activities dependent on Ste24p and Rce1p were recently reconstituted in vitro using crude yeast membranes (12.Boyartchuk V.L. Ashby M.N. Rine J. Science. 1997; 275: 1796-1800Crossref PubMed Scopus (304) Google Scholar). Whereas membranes containing either Ste24p or Rce1p promoted the CAAX proteolysis of a particular farnesylated peptide substrate, only Rce1p-containing membranes could promote the CAAX proteolysis of yeast Ras2p. The Ste24p-dependent N-terminal proteolytic activity was not examined in this study. In addition to its role in CAAX proteolysis, Ste24p is likely to act directly or indirectly as a protease in the first N-terminal cleavage of the a-factor precursor, but this has not yet been examined by direct in vitro studies (11.Fujimura-Kamada K. Nouvet F.J. Michaelis S. J. Cell Biol. 1997; 136: 271-285Crossref PubMed Scopus (129) Google Scholar). Accordingly, the aim of this study was to reconstitute an in vitro system that could be used to examine the role of Ste24p in the N-terminal processing (P1→P2) of a-factor. This would enable us to gain further insight into the role of Ste24p and to initiate a characterization of the biochemical properties of the N-terminal processing activity. Here, we have faithfully reconstitutedin vitro the N-terminal proteolysis of the P1a-factor precursor using yeast membranes as the source of Ste24p and the P1 a-factor precursor. We demonstrate biochemically that this activity requires Ste24p and a metal co-factor and that the cleavage event displays substrate specificity. Finally, we show in vivo and in vitro that the human homolog of Ste24p can properly direct the N-terminal processing of the yeasta-factor precursor. We thank Drs. D. Raben, P. Maloney, and L. Roman and members of the Michaelis laboratory for critical reading of the manuscript." @default.
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• W1984429232 title "Reconstitution of the Ste24p-dependent N-terminal Proteolytic Step in Yeast a-Factor Biogenesis" @default.
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