The Golgi Localization of GnTI Requires a Polar Amino Acid Residue within Its Transmembrane Domain

Schoberer, Jennifer; Liebminger, Eva; Vavra, Ulrike; Veit, Christiane; Grünwald‐Gruber, Clemens; Altmann, Friedrich; Botchway, Stanley W.; Strasser, Richard

doi:10.1104/pp.19.00310

Cited by 15 publications

(30 citation statements)

References 80 publications

(123 reference statements)

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“…The observation that differences in these sequence features can be detected between differentially localized proteins of very high overall sequence similarity ( Figure 6) lends weight to these features being important determining factors in sub-Golgi localization. Recently, Glu at the exoplasmic TM boundary was found to confer cis/medial-Golgi localization of GnTI (Schoberer et al, 2019). Exoplasmic anchoring of medial protein TM span sequences reveals a prominent Glu at this position in our data, suggesting that multiple medial-Golgi proteins are localized in this way.…”

Section: Discussionsupporting

confidence: 62%

“…Interestingly, TGN proteins were somewhat more associated with medial-than trans-Golgi cisternae ( Figure 2D). This could be a consequence of medial-Golgi receiving retrograde trafficked material in COPIb vesicles, as recently discussed (Schoberer et al, 2019).…”

Section: Discussionmentioning

confidence: 80%

“…If early to late cisternal localization is conferred by a gradient of preference for Ser and Phe, a specific central Golgi signal may add a further level of distinction. Alternatively, this may identify a specific retrieval pathway for medial proteins (Schoberer et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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Separating Golgi Proteins from Cis to Trans Reveals Underlying Properties of Cisternal Localization

et al. 2019

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The order of enzymatic activity across Golgi cisternae is essential for complex molecule biosynthesis. However, an inability to separate Golgi cisternae has meant that the cisternal distribution of most resident proteins, and their underlying localization mechanisms, are unknown. Here, we exploit differences in surface charge of intact cisternae to perform separation of early to late Golgi subcompartments. We determine protein and glycan abundance profiles across the Golgi; over 390 resident proteins are identified, including 136 new additions, with over 180 cisternal assignments. These assignments provide a means to better understand the functional roles of Golgi proteins and how they operate sequentially. Protein and glycan distributions are validated in vivo using high-resolution microscopy. Results reveal distinct functional compartmentalization among resident Golgi proteins. Analysis of transmembrane proteins shows several sequence-based characteristics relating to pI, hydrophobicity, Ser abundance, and Phe bilayer asymmetry that change across the Golgi. Overall, our results suggest that a continuum of transmembrane features, rather than discrete rules, guide proteins to earlier or later locations within the Golgi stack.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 80%

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Separating Golgi Proteins from Cis to Trans Reveals Underlying Properties of Cisternal Localization

et al. 2019

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“…Studies on the role of the TMDs in Golgi retention have examined only a limited range of proteins but most have suggested that the key aspect for retention is the physiochemical properties of the TMD. However, recent studies conducted in plants highlighted a glutamine residue in the TMD of N‐acetylglucosaminyltransferase I (GnTI) which was important for its targeting to the cis/medial‐Golgi . Mutagenesis of this residue caused GnTI to localise later in the Golgi and be directed to the vacuole for degradation .…”

Section: Transmembrane Domain‐dependent Sortingmentioning

confidence: 99%

A tale of short tails, through thick and thin: investigating the sorting mechanisms of Golgi enzymes

Welch

Munro

2019

FEBS Letters

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The Golgi apparatus is an important site for the modification of most secreted and membrane proteins. Glycan processing is the major class of modification and is mediated by a large number of Golgi‐resident glycosyltransferases and glycosidases. These Golgi enzymes are largely type II transmembrane domain (TMD) proteins consisting of a short N‐terminal cytosolic tail, a relatively short TMD and a lumenal ‘stem/stalk’ region which acts as a spacer between the catalytic domain and the lipid bilayer. The cytosolic tail, TMD, and stem together make what is termed the CTS domain which is responsible for the specific localisation of these enzymes within sub‐Golgi compartments via multiple mechanisms. In addition, the catalytic domains of some Golgi enzymes are secreted as a consequence of proteolytic cleavage within their TMDs or stem regions. Finally, there is evidence to suggest that when the retention of Golgi enzymes is perturbed they are targeted for lysosomal degradation.

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“…It seems likely that the missense mutations described here impair the ability of the mutant TMD to interact properly with the lipids of the Golgi bilayer, resulting in an unstable situation that allows the mutant protein to escape the Golgi. An alternate explanation is that the N‐terminal TMD of GlcNAc‐1‐phosphotransferase interacts with another Golgi protein to maintain its proper localization and the various mutations impair this interaction, resulting in the escape of the mutant protein from the Golgi (Schoberer et al, 2019; Sharpe et al, 2010; Welch & Munro, 2019). Further work will be required to clarify this situation.…”

Section: Discussionmentioning

confidence: 99%

Disease‐causing missense mutations within the N‐terminal transmembrane domain of GlcNAc‐1‐phosphotransferase impair endoplasmic reticulum translocation or Golgi retention

et al. 2020

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Transport of newly synthesized lysosomal enzymes to the lysosome requires tagging of these enzymes with the mannose 6‐phosphate moiety by UDP‐GlcNAc:lysosomal enzyme N‐acetylglucosamine‐1‐phosphotransferase (GlcNAc‐1‐phosphotransferase), encoded by two genes, GNPTAB and GNPTG. GNPTAB encodes the α and β subunits, which are initially synthesized as a single precursor that is cleaved by Site‐1 protease in the Golgi. Mutations in this gene cause the lysosomal storage disorders mucolipidosis II (MLII) and mucolipidosis III αβ (MLIII αβ). Two recent studies have reported the first patient mutations within the N‐terminal transmembrane domain (TMD) of the α subunit of GlcNAc‐1‐phosphotransferase that cause either MLII or MLIII αβ. Here, we demonstrate that two of the MLII missense mutations, c.80T>A (p.Val27Asp) and c.83T>A (p.Val28Asp), prevent the cotranslational insertion of the nascent GlcNAc‐1‐phosphotransferase polypeptide chain into the endoplasmic reticulum. The remaining four mutations, one of which is associated with MLII, c.100G>C (p.Ala34Pro), and the other three with MLIII αβ, c.70T>G (p.Phe24Val), c.77G>A (p.Gly26Asp), and c.107A>C (p.Glu36Pro), impair retention of the catalytically active enzyme in the Golgi with concomitant mistargeting to endosomes/lysosomes. Our results uncover the basis for the disease phenotypes of these patient mutations and establish the N‐terminal TMD of GlcNAc‐1‐phosphotransferase as an important determinant of Golgi localization.

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The Golgi Localization of GnTI Requires a Polar Amino Acid Residue within Its Transmembrane Domain

Cited by 15 publications

References 80 publications

Separating Golgi Proteins from Cis to Trans Reveals Underlying Properties of Cisternal Localization

Separating Golgi Proteins from Cis to Trans Reveals Underlying Properties of Cisternal Localization

A tale of short tails, through thick and thin: investigating the sorting mechanisms of Golgi enzymes

Disease‐causing missense mutations within the N‐terminal transmembrane domain of GlcNAc‐1‐phosphotransferase impair endoplasmic reticulum translocation or Golgi retention

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