A C-terminally-anchored Golgi protein is inserted into the endoplasmic reticulum and then transported to the Golgi apparatus.

Linstedt, Adam D.; Foguet, M.; Renz, Manfred; Seelig, H. P.; Glick, Benjamin S.; Hauri, Hans Peter

doi:10.1073/pnas.92.11.5102

Cited by 100 publications

(100 citation statements)

References 25 publications

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“…Deletion of the Inp54p hydrophobic tail resulted in a cytoplasmic distribution of the protein, consistent with previous observations that the C terminus of tail-anchored proteins contains the membrane targeting information (38,45,47,48,59,60). The last 13 amino acids of Inp54p also direct GFP to the ER.…”

Section: Discussionsupporting

confidence: 73%

The Yeast Inositol Polyphosphate 5-Phosphatase Inp54p Localizes to the Endoplasmic Reticulum via a C-terminal Hydrophobic Anchoring Tail

Wiradjaja

Ooms

Whisstock

et al. 2001

Journal of Biological Chemistry

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Phosphoinositides are ubiquitous membrane components of various intracellular compartments, which regulate many diverse cellular functions including membrane trafficking events, secretion, actin cytoskeletal organization, cellular proliferation, and inhibition of apoptosis (reviewed in Refs. 1-4). Many of these functions are mediated by binding and recruiting signaling proteins which contain specific phosphoinositidebinding domains such as SH2 domains, pleckstrin homology domains, FYVE domains, C2 domains or polybasic domains, thereby localizing these effector proteins to specific membranes (reviewed in Refs. 3 and 4).Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P 2 ) 1 serves as a precursor to second messenger molecules such as inositol (1,4,5)-trisphosphate and phosphatidylinositol (3,4,5)-trisphosphate, but also independent of further modification regulates the actin cytoskeleton and membrane trafficking (1, 5). PtdIns(4,5)P 2 binds to actin-binding proteins such as profilin and gelsolin (6) and displaces capping proteins from actin filaments, allowing polymerization and formation of actin stress fibers (7-9). PtdIns(4,5)P 2 also plays a role in regulating vesicle budding and in the recruitment and activation of proteins involved in the coating of vesicles (2).Cellular levels of PtdIns(4,5)P 2 are regulated by a series of lipid phosphorylation and dephosphorylation reactions mediated by specific lipid kinases and phosphatases. Inositol polyphosphate 5-phosphatases (5-phosphatases) regulate cellular PtdIns(4,5)P 2 levels by hydrolyzing the 5-position phosphate from the inositol ring forming phosphatidylinositol 4-phosphate (PtdIns(4)P) (10, 11). The budding yeast Saccharomyces cerevisiae has four 5-phosphatase genes, INP51, INP52, INP53, and INP54. Inp51p, Inp52p, and Inp53p each comprise an N-terminal SacI domain, a central 5-phosphatase domain, and a C-terminal proline-rich region (12, 13). These enzymes share significant sequence homology with the mammalian homologue synaptojanin, which regulates the recycling of synaptic vesicles in nerve terminals (14). Synaptojanin, Inp52p, and Inp53p contain two catalytic domains, a central 5-phosphatase domain and an N-terminal SacI domain which hydrolyzes PtdIns(3,5)P 2 , PtdIns(4)P, and PtdIns(3)P forming PtdIns (15). Null mutation of any two SacI domain-containing 5-phosphatases results in plasma membrane invaginations and thickened cell walls, defects in polarization of the actin cytoskeleton, and impaired endocytosis (12, 13). However, double SacI domain-containing 5-phosphatase null mutants display normal secretion of invertase suggesting that Inp51p, Inp52p, and Inp53p do not play a role in regulating secretion (16). A triple SacI domain-containing 5-phosphatase null mutant is nonviable suggesting Inp54p cannot function to rescue the loss of these three 5-phosphatases.

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Section: Discussionsupporting

confidence: 73%

The Yeast Inositol Polyphosphate 5-Phosphatase Inp54p Localizes to the Endoplasmic Reticulum via a C-terminal Hydrophobic Anchoring Tail

Wiradjaja

Ooms

Whisstock

et al. 2001

Journal of Biological Chemistry

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“…EEA1 interacts with the GTP-bound form of Rab5p via a small N-terminal domain containing a zinc finger and through a C-terminal fragment adjacent to the so-called FYVE finger. In contrast, Sys3p, which shares with EEA1 the extended ␣-helical regions but does not contain sequences related to its Rab5p-interacting regions, does not interact with Ypt6p or its GTPasedeficient mutant Ypt6(Q69L)p. Giantin, a 376-kDa, rod-shaped protein bound to the cytoplasmic surface of Golgi membranes (Linstedt et al, 1995), has been reported recently to have a role in COPI vesicle docking (Sö nnichsen et al, 1998). Likewise, the Sys3p-related Uso1 protein, which like Sys3p is only partially membrane associated, is needed for the docking of ER-derived vesicles to the cis-Golgi compartment (Sapperstein et al, 1996;Cao et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Analysis of a Novel Coiled-Coil Protein Involved in Ypt6 GTPase-regulated Protein Transport in Yeast

Tsukada

Will

Gallwitz

1999

MBoC

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The yeast transport GTPase Ypt6p is dispensable for cell growth and secretion, but its lack results in temperature sensitivity and missorting of vacuolar carboxypeptidase Y. We previously identified four yeast genes (SYS1, 2, 3, and 5) that on high expression suppressed these phenotypic alterations. SYS3 encodes a 105-kDa protein with a predicted high ␣-helical content. It is related to a variety of mammalian Golgi-associated proteins and to the yeast Uso1p, an essential protein involved in docking of endoplasmic reticulum-derived vesicles to the cis-Golgi. Like Uso1p, Sys3p is predominatly cytosolic. According to gel chromatographic, two-hybrid, and chemical cross-linking analyses, Sys3p forms dimers and larger protein complexes. Its loss of function results in partial missorting of carboxypeptidase Y. Double disruptions of SYS3 and YPT6 lead to a significant growth inhibition of the mutant cells, to a massive accumulation of 40-to 50-nm vesicles, to an aggravation of vacuolar protein missorting, and to a defect in ␣-pheromone processing apparently attributable to a perturbation of protease Kex2p cycling between the Golgi and a post-Golgi compartment. The results of this study suggest that Sys3p, like Ypt6p, acts in vesicular transport (presumably at a vesicledocking stage) between an endosomal compartment and the most distal Golgi compartment.

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“…Indeed, immunofluorescence analysis of COS cells demonstrated Golgi staining of the endogenous TMEM59, which overlapped with the well characterized Golgi markers giantin (cis-medial Golgi) (31,56) and p230 (trans-Golgi and TGN) (57) (Fig. 5, A and B).…”

Section: Tmem59mentioning

confidence: 99%

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

Ullrich

Münch

Neumann

et al. 2010

Journal of Biological Chemistry

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Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases ␣-and ␤-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid ␤ peptide (A␤). At present, little is known about the cellular mechanisms that control APP shedding and A␤ generation. Here, we identified a novel protein, transmembrane protein 59 (TMEM59), as a new modulator of APP shedding. TMEM59 was found to be a ubiquitously expressed, Golgi-localized protein. TMEM59 transfection inhibited complex N-and O-glycosylation of APP in cultured cells. Additionally, TMEM59 induced APP retention in the Golgi and inhibited A␤ generation as well as APP cleavage by ␣-and ␤-secretase cleavage, which occur at the plasma membrane and in the endosomes, respectively. Moreover, TMEM59 inhibited the complex N-glycosylation of the prion protein, suggesting a more general modulation of Golgi glycosylation reactions. Importantly, TMEM59 did not affect the secretion of soluble proteins or the ␣-secretase like shedding of tumor necrosis factor ␣, demonstrating that TMEM59 did not disturb the general Golgi function. The phenotype of TMEM59 transfection on APP glycosylation and shedding was similar to the one observed in cells lacking conserved oligomeric Golgi (COG) proteins COG1 and COG2. Both proteins are required for normal localization and activity of Golgi glycosylation enzymes. In summary, this study shows that TMEM59 expression modulates complex N-and O-glycosylation and suggests that TMEM59 affects APP shedding by reducing access of APP to the cellular compartments, where it is normally cleaved by ␣-and ␤-secretase. Processing of the amyloid precursor protein (APP)3 by two different proteases, called ␣-and ␤-secretase, is a central regulatory event in the generation of the amyloid ␤ peptide (A␤), which has a key role in Alzheimer disease (AD) pathogenesis (1). Both ␣-and ␤-secretase cleave the type I membrane protein APP within its ectodomain close to its transmembrane domain (2). This leads to the secretion of soluble forms of APP (APPs) and is referred to as APP shedding. The ␤-secretase is the aspartyl protease BACE1 and cleaves APP at the N terminus of the A␤ peptide domain, thus catalyzing the first step in A␤ peptide generation (3, 4). After the initial cleavage of APP by BACE1, the remaining C-terminal APP fragment is cleaved by ␥-secretase within its transmembrane domain at the C terminus of the A␤ domain, leading to the secretion of the A␤-peptide (5). In contrast to ␤-secretase, ␣-secretase cleaves within the A␤-sequence of APP, and thereby precludes A␤ peptide generation. Additionally, ␣-but not ␤-secretase cleavage generates a secreted form of APP (APPs␣), which has neurotrophic and neuroprotective properties (6 -8). The ␣-secretase is a member of the ADAM family (A disintegrin and metalloprotease) of proteases (9 -12). At present little is known about how the cell controls access of APP to its secretases and the amount of ␣-and ␤-secretase cleavage (reviewed in Refs. 13 and 14). Recent studies increasingl...

show abstract

A C-terminally-anchored Golgi protein is inserted into the endoplasmic reticulum and then transported to the Golgi apparatus.

Cited by 100 publications

References 25 publications

The Yeast Inositol Polyphosphate 5-Phosphatase Inp54p Localizes to the Endoplasmic Reticulum via a C-terminal Hydrophobic Anchoring Tail

The Yeast Inositol Polyphosphate 5-Phosphatase Inp54p Localizes to the Endoplasmic Reticulum via a C-terminal Hydrophobic Anchoring Tail

Structural and Functional Analysis of a Novel Coiled-Coil Protein Involved in Ypt6 GTPase-regulated Protein Transport in Yeast

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

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