Intramembrane proteolysis and post-targeting functions of signal peptides

2003 ◽  
Vol 31 (6) ◽  
pp. 1243-1247 ◽  
Author(s):  
B. Martoglio
Keyword(s):  
Endoplasmic Reticulum ◽  
Lipid Bilayer ◽  
Signal Peptide ◽  
Eukaryotic Cells ◽  
Endoplasmic Reticulum Membrane ◽  
Signal Peptides ◽  
Peptide Fragments ◽  
Intramembrane Proteolysis ◽  
Signal Sequences ◽  
Membrane Spanning

Signal sequences are the addresses of proteins destined for secretion. In eukaryotic cells, they mediate targeting to the endoplasmic reticulum membrane and insertion into the translocon. Thereafter, signal sequences are cleaved from the pre-protein and liberated into the endoplasmic reticulum membrane. We have recently reported that some liberated signal peptides are further processed by the intramembrane-cleaving aspartic protease signal peptide peptidase. Cleavage in the membrane-spanning portion of the signal peptide promotes the release of signal peptide fragments from the lipid bilayer. Typical processes that include intramembrane proteolysis is the regulatory or signalling function of cleavage products. Likewise, signal peptide fragments liberated upon intramembrane cleavage may promote such post-targeting functions in the cell.

scholarly journals Signal peptide peptidase (SPP) assembles with substrates and misfolded membrane proteins into distinct oligomeric complexes

2010 ◽  
Vol 427 (3) ◽  
pp. 523-534 ◽  
Author(s):  
Bianca Schrul ◽  
Katja Kapp ◽  
Irmgard Sinning ◽  
Bernhard Dobberstein
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Membrane Protein ◽  
Signal Peptide ◽  
Large Range ◽  
Endoplasmic Reticulum Membrane ◽  
Signal Peptides ◽  
Type Ii ◽  
Signal Peptide Peptidase

SPP (signal peptide peptidase) is an aspartyl intramembrane cleaving protease, which processes a subset of signal peptides, and is linked to the quality control of ER (endoplasmic reticulum) membrane proteins. We analysed SPP interactions with signal peptides and other membrane proteins by co-immunoprecipitation assays. We found that SPP interacts specifically and tightly with a large range of newly synthesized membrane proteins, including signal peptides, preproteins and misfolded membrane proteins, but not with all co-expressed type II membrane proteins. Signal peptides are trapped by the catalytically inactive SPP mutant SPPD/A. Preproteins and misfolded membrane proteins interact with both SPP and the SPPD/A mutant, and are not substrates for SPP-mediated intramembrane proteolysis. Proteins interacting with SPP are found in distinct complexes of different sizes. A signal peptide is mainly trapped in a 200 kDa SPP complex, whereas a preprotein is predominantly found in a 600 kDa SPP complex. A misfolded membrane protein is detected in 200, 400 and 600 kDa SPP complexes. We conclude that SPP not only processes signal peptides, but also collects preproteins and misfolded membrane proteins that are destined for disposal.

scholarly journals Species-specificity in endoplasmic reticulum signal peptide utilization revealed by proteins from Trypanosoma brucei and Leishmania

1998 ◽  
Vol 331 (2) ◽  
pp. 521-529 ◽  
Author(s):  
Ahmed AL-QAHTANI ◽  
Meredith TEILHET ◽  
Kojo MENSA-WILMOT
Keyword(s):  
Endoplasmic Reticulum ◽  
Trypanosoma Brucei ◽  
Signal Peptide ◽  
Protein Import ◽  
Signal Sequence ◽  
Surface Glycoprotein ◽  
Signal Peptides ◽  
Species Barrier ◽  
Signal Sequences ◽  
Nuclear Polyhedrosis

N-Terminal signal peptides direct secretory and most membrane proteins into the exocytic pathway at the endoplasmic reticulum. Signal sequences can function across kingdoms. However, our attempts at translocating variant surface glycoprotein (VSG) 117, VSG MVAT7, VSG 221 and BiP from Trypanosoma brucei and gp63 from Leishmania chagasi into canine pancreas microsomes failed. On replacing the signal peptide of VSG 117 with that from yeast prepro-α-mating factor (ppαMF) the chimaeric protein was imported, indicating that the signal sequence of VSG 117 was incompatible with the protein-import machinery of mammalian microsomes. Replacement of the gp63-h-region with a hybrid composed of the N-terminal nine residues from the h-region of gp67 from Autographa californica nuclear polyhedrosis virus and the C-terminal 10 residues from the h-region of gp63 from L. major produced a functional signal peptide. Thus, the h-region of kinetoplastid signal peptides appears to be the subdomain that is non-functional at the mammalian translocon. The calculated biophysical properties and computed discriminant scores (predictive of importability of signal peptides into mammalian microsomes) of the kinetoplastid signal sequences nevertheless are similar to those of ppαMF and Escherichia coliβ-lactamase both of which were imported. These signal peptides are the first collection from one biological family that have been found to fail to function across a species barrier. They indicate that signal peptides are not as universally interchangeable as previously believed. Intriguingly, endoplasmic reticulum signal peptides from Leishmania and Crithidia fasciculata are reminiscent of signal peptides from Gram-positive bacteria.

scholarly journals TheSaccharomyces cerevisiaePrenylcysteine Carboxyl Methyltransferase Ste14p Is in the Endoplasmic Reticulum Membrane

1998 ◽  
Vol 9 (8) ◽  
pp. 2231-2247 ◽  
Author(s):  
Julia D. Romano ◽  
Walter K. Schmidt ◽  
Susan Michaelis
Keyword(s):  
Endoplasmic Reticulum ◽  
Subcellular Fractionation ◽  
Endoplasmic Reticulum Membrane ◽  
Carboxyl Methylation ◽  
C Terminus ◽  
Eukaryotic Proteins ◽  
Internal Site ◽  
Membrane Spanning ◽  
Er Membrane

Eukaryotic proteins containing a C-terminal CAAX motif undergo a series of posttranslational CAAX-processing events that include isoprenylation, C-terminal proteolytic cleavage, and carboxyl methylation. We demonstrated previously that the STE14gene product of Saccharomyces cerevisiae mediates the carboxyl methylation step of CAAX processing in yeast. In this study, we have investigated the subcellular localization of Ste14p, a predicted membrane-spanning protein, using a polyclonal antibody generated against the C terminus of Ste14p and an in vitro methyltransferase assay. We demonstrate by immunofluorescence and subcellular fractionation that Ste14p and its associated activity are localized to the endoplasmic reticulum (ER) membrane of yeast. In addition, other studies from our laboratory have shown that the CAAX proteases are also ER membrane proteins. Together these results indicate that the intracellular site of CAAX protein processing is the ER membrane, presumably on its cytosolic face. Interestingly, the insertion of a hemagglutinin epitope tag at the N terminus, at the C terminus, or at an internal site disrupts the ER localization of Ste14p and results in its mislocalization, apparently to the Golgi. We have also expressed the Ste14p homologue from Schizosaccharomyces pombe, mam4p, in S. cerevisiae and have shown that mam4p complements a Δste14 mutant. This finding, plus additional recent examples of cross-species complementation, indicates that the CAAX methyltransferase family consists of functional homologues.

scholarly journals NHE6 Protein Possesses a Signal Peptide Destined for Endoplasmic Reticulum Membrane and Localizes in Secretory Organelles of the Cell

2001 ◽  
Vol 276 (52) ◽  
pp. 49221-49227 ◽  
Author(s):  
Emi Miyazaki ◽  
Masao Sakaguchi ◽  
Shigeo Wakabayashi ◽  
Munekazu Shigekawa ◽  
Katsuyoshi Mihara
Keyword(s):  
Endoplasmic Reticulum ◽  
Signal Peptide ◽  
Endoplasmic Reticulum Membrane

scholarly journals Precursors of select GPI-anchored proteins positively regulate GPI biosynthesis under the control of ERAD

2021 ◽  
Author(s):  
Yi-Shi Liu ◽  
Yicheng Wang ◽  
Xiaoman Zhou ◽  
LinPei Zhang ◽  
Ganglong Yang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Signal Peptide ◽  
Active Element ◽  
Signal Peptides ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Genome Wide ◽  
A Genome ◽  
Mechanistic Basis ◽  
Gpi Transamidase ◽  
Regulatory Connection

Abstract We previously reported that glycosylphosphatidylinositol (GPI) biosynthesis is regulated by endoplasmic reticulum associated degradation (ERAD); however, the underlying mechanistic basis remains unclear. Based on a genome-wide CRISPR–Cas9 screen, we show that a widely expressed GPI-anchored protein CD55 precursor and ER-resident ARV1 together upregulate GPI biosynthesis under ERAD-deficient conditions. In cells defective in GPI transamidase, GPI-anchored protein precursors fail to obtain GPI, remaining the uncleaved GPI-attachment signal at the C-termini. We show that ERAD deficiency causes accumulation of the CD55 precursor, which in turn upregulates GPI biosynthesis, where the GPI-attachment signal peptide is the active element. Among the 32 GPI-anchored proteins tested, only the GPI-attachment signal peptides of CD55 and CD48 enhance GPI biosynthesis. ARV1 is essential for the GPI upregulation by CD55 precursor. Our data demonstrate an ARV1-dependent regulatory connection between GPI biosynthesis and precursors of select GPI-anchored proteins that are under the control of ERAD.

Regulated intramembrane proteolysis: from the endoplasmic reticulum to the nucleus

2002 ◽  
Vol 38 ◽  
pp. 155-168 ◽  
Author(s):  
Robert B Rawson
Keyword(s):  
Endoplasmic Reticulum ◽  
Regulatory Element ◽  
Transmembrane Proteins ◽  
Intramembrane Proteolysis ◽  
Regulated Intramembrane Proteolysis ◽  
Class 1 ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Membrane Spanning ◽  
Highly Hydrophobic

Regulated intramembrane proteolysis (Rip) is an ancient and widespread process by which cells transmit information from one compartment (the endoplasmic reticulum) to another (the nucleus). Two separate cleavages that are carried out by two separate proteases are required for Rip. The first protease cleaves its protein substrate within an extracytoplasmic domain; the second cleaves it within a membrane-spanning domain, releasing a functionally active fragment of the target protein. In eukaryotes, examples of Rip can be divided into two classes, according to the proteases that are involved and the orientation of the substrates with the membrane. Class 1 Rip involves type 1 transmembrane proteins and requires presenilin for cleavage within a membrane-spanning domain. In Class 2 Rip, the highly hydrophobic metalloprotease, site-2 protease, is required for cleavage within a membrane-spanning domain and substrates are type 2 transmembrane proteins. Both classes of Rip are implicated in diseases that are important in modern societies, such as hyperlipidaemias (via the sterol regulatory element binding protein pathway) and Alzheimer's disease (via processing of the amyloid precursor protein.)

Sign in / Sign up

Export Citation Format

Share Document