The Yeast SPC22/23 Homolog Spc3p Is Essential for Signal Peptidase Activity

Meyer, Hellmuth-A.; Hartmann, Enno

doi:10.1074/jbc.272.20.13159

Cited by 51 publications

(37 citation statements)

References 37 publications

(41 reference statements)

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“…aspartic acids were conserved upon alignment of yeast Spc3p to its canine, chicken, Caenorhabditis elegans, and Schizosaccharomyces pombe counterparts (Fig. 2B) (21).…”

Section: Resultsmentioning

confidence: 99%

The Catalytic Mechanism of Endoplasmic Reticulum Signal Peptidase Appears to Be Distinct from Most Eubacterial Signal Peptidases

VanValkenburgh

Chen

Mullins³

et al. 1999

Journal of Biological Chemistry

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Many type I signal peptidases from eubacterial cells appear to contain a serine/lysine catalytic dyad. In contrast, our data show that the signal peptidase complex from the endoplasmic reticulum lacks an apparent catalytic lysine. Instead, a serine, histidine, and two aspartic acids are important for signal peptidase activity by the Sec11p subunit of the yeast signal peptidase complex. Amino acids critical to the eubacterial signal peptidases and Sec11p are, however, positioned similarly along their primary sequences, suggesting the presence of a common structural element(s) near the catalytic sites of these enzymes.Cleavable signal sequences, which are usually located at the N termini of precursor proteins, function in the delivery of their protein cargo to specific destinations within both eukaryotic and eubacterial cells. A large number of signal sequences possess a common motif consisting of an n-region that is often positively charged and a hydrophobic core (the h-region) followed by a polar c-region containing the cleavage site (1). Small uncharged amino acids are usually present at the Ϫ1 and Ϫ3 positions from the cleavage site. Signals exhibiting this motif are recognized and cleaved by type I signal peptidases. Type I signal peptidases are found within the endoplasmic reticulum (ER) 1 membrane, the mitochondrial inner membrane, and the cytoplasmic membrane of eubacterial cells (reviewed in Ref. 2). There is a strong functional conservation of the signal sequence cleavage reaction, revealed by the fact that signal sequences of proteins targeted normally to the ER can be cleaved by eubacterial signal peptidase (3), and eubacterial signal sequences can be cleaved by ER signal peptidase (4).Site-directed mutagenesis studies suggest that many eubacterial signal peptidases contain a serine/lysine dyad with which to catalyze the cleavage reaction (5-9). A similar catalytic dyad is thought to be present in the LexA and UmuD proteins of Escherichia coli (10, 11) and in both catalytic subunits of mitochondrial signal peptidase (12). Recent x-ray crystallographic analysis confirms the role of serine as a nucleophile and is consistent with a lysine acting as a general base in catalysis by E. coli leader peptidase (13).At least one eubacterial signal peptidase, SipW of Bacillus subtilus, may exhibit a catalytic site more like that of Sec11p of the ER signal peptidase. B. subtilus contains five distinct chromosomally encoded signal peptidases, SipW being the only one like Sec11p (14, 15). As shown in Fig. 1, Sec11p contains a serine residue that aligns to the catalytic serine of leader peptidase; however, within the limited regions of homology that exist between Sec11p and leader peptidase, Sec11p contains a histidine that has been aligned to the catalytic lysine of leader peptidase (16,17). From this, the type I signal peptidase family may contain a subgroup, represented by Sec11p and SipW, that uses a distinct catalytic mechanism (14). It has been noted previously, however, that an alignment of Sec11p to the E. col...

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“…aspartic acids were conserved upon alignment of yeast Spc3p to its canine, chicken, Caenorhabditis elegans, and Schizosaccharomyces pombe counterparts (Fig. 2B) (21).…”

Section: Resultsmentioning

confidence: 99%

The Catalytic Mechanism of Endoplasmic Reticulum Signal Peptidase Appears to Be Distinct from Most Eubacterial Signal Peptidases

VanValkenburgh

Chen

Mullins³

et al. 1999

Journal of Biological Chemistry

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“…SPCS1 and SPCS2 span the ER membrane twice, exposing the bulk of each protein to the cytosolic site of the ER membrane, and are not required for SPase activity (37,46). In contrast, SPCS3, SEC11A, and SEC11C are single-spanning membrane proteins that are required for SPase activity (9,47). The latter subunits anchor their amino-terminal transmembrane domains in the ER membrane, exposing much larger domains to the ER lumen (36).…”

Section: Discussionmentioning

confidence: 99%

Competitive Inhibition of the Endoplasmic Reticulum Signal Peptidase by Non-cleavable Mutant Preprotein Cargos

Cui

Chen

Sun

et al. 2015

Journal of Biological Chemistry

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Background: Signal peptidase (SPase) excises the signal peptide of secretory preproteins. Results: A variant preproinsulin with a proline following the signal peptide cleavage site binds to and inhibits SPase. Conclusion: Inhibition of SPase impairs, in trans, the intracellular processing, trafficking, and maturation of secretory proteins and viral polypeptides. Significance: Our findings suggest eukaryotic SPase as a potential antiviral target.

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“…The SPC consists of four polypeptides termed Spc1, Spc2, Spc3, and Sec11 (Bohni et al 1988;YaDeau et al 1991). Spc3 and Sec11 are essential integral membrane proteins that are required for signal sequence cleavage activity, with the Sec11 subunit containing the protease active site (Fang et al 1997;Meyer and Hartmann 1997). Based on structural comparisons with E. coli leader peptidase, the active site of SPC is thought to be located very near the lumenal surface of the ER membrane and presumably close to translocon exit sites.…”

Section: Maturation Of Secretory Proteins In the Er: Signal Sequence mentioning

confidence: 99%

Secretory Protein Biogenesis and Traffic in the Early Secretory Pathway

2013

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The secretory pathway is responsible for the synthesis, folding, and delivery of a diverse array of cellular proteins. Secretory protein synthesis begins in the endoplasmic reticulum (ER), which is charged with the tasks of correctly integrating nascent proteins and ensuring correct post-translational modification and folding. Once ready for forward traffic, proteins are captured into ER-derived transport vesicles that form through the action of the COPII coat. COPII-coated vesicles are delivered to the early Golgi via distinct tethering and fusion machineries. Escaped ER residents and other cycling transport machinery components are returned to the ER via COPI-coated vesicles, which undergo similar tethering and fusion reactions. Ultimately, organelle structure, function, and cell homeostasis are maintained by modulating protein and lipid flux through the early secretory pathway. In the last decade, structural and mechanistic studies have added greatly to the strong foundation of yeast genetics on which this field was built. Here we discuss the key players that mediate secretory protein biogenesis and trafficking, highlighting recent advances that have deepened our understanding of the complexity of this conserved and essential process. TABLE OF CONTENTS Abstract 383Introduction 384

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The Yeast SPC22/23 Homolog Spc3p Is Essential for Signal Peptidase Activity

Cited by 51 publications

References 37 publications

The Catalytic Mechanism of Endoplasmic Reticulum Signal Peptidase Appears to Be Distinct from Most Eubacterial Signal Peptidases

The Catalytic Mechanism of Endoplasmic Reticulum Signal Peptidase Appears to Be Distinct from Most Eubacterial Signal Peptidases

Competitive Inhibition of the Endoplasmic Reticulum Signal Peptidase by Non-cleavable Mutant Preprotein Cargos

Secretory Protein Biogenesis and Traffic in the Early Secretory Pathway

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