COG5-CDG: expanding the clinical spectrum

Rymen, Daisy; Keldermans, Liesbeth; Race, Valérie; Régal, Luc; Deconinck, Nicolas; Dionisi‐Vici, Carlo; Fung, Cheuk Wing; Sturiale, Luisa; Rosnoblet, Claire; Foulquier, François; Matthijs, Gert; Jaeken, Jaak

doi:10.1186/1750-1172-7-94

Cited by 37 publications

(66 citation statements)

References 23 publications

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“…Our structure reveals Cog5 as an example of the CATCHR fold and elucidates the nature of its interaction with Cog7. We find that the Cog5-Cog7 interface is conserved from yeast to humans and that its disruption causes glycosylation defects in human tissue culture cells and, probably, in a previously identified COG5-CDG patient (24,25).…”

Section: Significancementioning

confidence: 60%

“…Mutations in any of the four human lobe B subunits give rise to CDGs (17). COG5-CDG and COG7-CDG patients display reduced levels of both COG5 and COG7 subunits, consistent with the direct interaction between these subunits (25,33). We therefore anticipated that disruption of the COG5-COG7 interaction in human cells might have measurable consequences.…”

Section: Significancementioning

confidence: 96%

“…Recently, COG5 mutations were reported in several CDG patients (24,25,39); substantial clinical overlap between COG5-CDG and COG7-CDG was noted (25). Most of the known COG5-CDG patients carry homozygous nonsense or exon skipping mutations (25,39).…”

Section: Significancementioning

confidence: 99%

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Cog5–Cog7 crystal structure reveals interactions essential for the function of a multisubunit tethering complex

Pokrovskaya

Climer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The conserved oligomeric Golgi (COG) complex is required, along with SNARE and Sec1/Munc18 (SM) proteins, for vesicle docking and fusion at the Golgi. COG, like other multisubunit tethering complexes (MTCs), is thought to function as a scaffold and/or chaperone to direct the assembly of productive SNARE complexes at the sites of membrane fusion. Reflecting this essential role, mutations in the COG complex can cause congenital disorders of glycosylation. A deeper understanding of COG function and dysfunction will likely depend on elucidating its molecular structure. Despite some progress toward this goal, including EM studies of COG lobe A (subunits 1-4) and higher-resolution structures of portions of Cog2 and Cog4, the structures of COG's eight subunits and the principles governing their assembly are mostly unknown. Here, we report the crystal structure of a complex between two lobe B subunits, Cog5 and Cog7. The structure reveals that Cog5 is a member of the complexes associated with tethering containing helical rods (CATCHR) fold family, with homology to subunits of other MTCs including the Dsl1, exocyst, and Golgi-associated retrograde protein (GARP) complexes. The Cog5-Cog7 interaction is analyzed in relation to the Dsl1 complex, the only other CATCHR-family MTC for which subunit interactions have been characterized in detail. Biochemical and functional studies validate the physiological relevance of the observed Cog5-Cog7 interface, indicate that it is conserved from yeast to humans, and demonstrate that its disruption in human cells causes defects in trafficking and glycosylation.I n eukaryotes, the transport of proteins and lipids among intracellular compartments is mediated by vesicular and tubular carriers under the direction of an elaborate protein machinery (1). Among the most complex and least well-characterized components of this machinery are the multisubunit tethering complexes (MTCs) (2). MTCs are thought to mediate the initial attachment (or tethering) between a trafficking vesicle and its target membrane through a constellation of interactions (3, 4). These may include binding of the MTC to activated Rab GTPases, coiled-coil proteins such as Golgins, vesicle coat proteins, SNAREs, Sec1/ Munc18 (SM) proteins, and/or membrane lipids. Elucidating the 3D structures of MTCs represents an important step toward a better understanding of their molecular functions.Four of the known MTCs-termed complexes associated with tethering containing helical rods (CATCHR) or quatrefoil complexes (2, 5)-contain subunits whose shared 3D structure implies a single evolutionary progenitor (6-16). These CATCHR-family MTCs include the Dsl1, Golgi-associated retrograde protein (GARP), exocyst, and conserved oligomeric Golgi (COG) complexes, and they contain three, four, eight, and eight subunits, respectively. Although X-ray or NMR structures have been reported for 14 of these 23 subunits, only one of the structures contains the full-length polypeptide (14). Perhaps more critically, only two subunit interactions-both wit...

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Section: Significancementioning

confidence: 60%

Section: Significancementioning

confidence: 96%

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Cog5–Cog7 crystal structure reveals interactions essential for the function of a multisubunit tethering complex

Pokrovskaya

Climer

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The identification of milder cases of COG6 and COG7 deficiency harboring different mutations [56,57] however shows that the severity of the disease does not simply relate to the subunit affected but rather to the capability of forming a fully functional COG complex. Besides the severe diseases observed for COG6 and COG7 defects, moderate clinical manifestations have been associated with mutations in COG1 [58,59], COG2 [60], COG4 [61,62], and COG5 [63][64][65].…”

Section: Localization Of Glycosyltransferasesmentioning

confidence: 99%

“…By contrast, Gal-transferases and Sia-transferases residing in trans-Golgi cisternae are more influenced by lobe B alterations [67]. Furthermore, lobe B deficiency mainly results in altered steady state levels of these enzymes due to their translocation to the ER and subsequent proteasomal degradation [65]. The broad involvement of lobe B in regulating glycosyltransferase and other transGolgi proteins probably account for the increased severity of lobe B mutations.…”

mentioning

confidence: 99%

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

Hennet

Cabalzar

2015

Trends in Biochemical Sciences

112

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Glycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways not only revealed tremendous diversity in functional impairments, but also pointed to phenotypic similarities, emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview of the significance of glycosylation in human development and physiology. Congenital disorders of glycosylation -a consice chart of glycocalyx dysfunctionThierry Hennet, Jürg Cabalzar Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland AbstractGlycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways has revealed a tremendous diversity of functional impairments bus also pointed to phenotypic similarities emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview on the significance of glycosylation in human development and physiology. Highlights Congenital disorders underline the role of glycosylation in human development.  Next-gen sequencing techniques expanded the discovery of glycosylation gene defects.  The clinical variability of glycosylation disorders implies they are underdiagnosed. Glycosylation disordersGlycosylation is by far the most complex form of protein [1,2] and lipid modification [3,4] in all domains of life. The tremendous diversity of glycoconjugate structures resulting from intricate biosynthetic pathways is a major factor hampering the assignment of functions to glycans chains. Much has been learnt from the study of disrupted glycosylation genes in model organisms, thereby establishing numerous essential contributions of glycans in regulating cell and organ functions [5]. The study of human diseases of glycosylation brings additional insights by providing a more differentiated view on glycan functions. Indeed, most human mutations are hypomorphic, thus causing partial loss of glycosylation reactions that lead to variable clinical manifestations.Diseases of glycosylation are also referred to as congenital disorders of glycosylation (CDG). Given the heterogeneity of glycans, the clinical scope of CDG is considerable, ranging from nearly normal phenotypes to sever...

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Maintaining order: COG complex controls Golgi trafficking, processing, and sorting

2019

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The conserved oligomeric Golgi (COG) complex, a multisubunit tethering complex of the CATCHR (complexes associated with tethering containing helical rods) family, controls membrane trafficking and ensures Golgi homeostasis by orchestrating retrograde vesicle targeting within the Golgi. In humans, COG defects lead to severe multisystemic diseases known as COG‐congenital disorders of glycosylation (COG‐CDG). The COG complex both physically and functionally interacts with all classes of molecules maintaining intra‐Golgi trafficking, namely SNAREs, SNARE‐interacting proteins, Rabs, coiled‐coil tethers, and vesicular coats. Here, we review our current knowledge of COG‐related trafficking and glycosylation defects in humans and model organisms, and analyze possible scenarios for the molecular mechanism of the COG orchestrated vesicle targeting.

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COG5-CDG: expanding the clinical spectrum

Cited by 37 publications

References 23 publications

Cog5–Cog7 crystal structure reveals interactions essential for the function of a multisubunit tethering complex

Cog5–Cog7 crystal structure reveals interactions essential for the function of a multisubunit tethering complex

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

Maintaining order: COG complex controls Golgi trafficking, processing, and sorting

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