Mutation in transforming growth factor beta induced protein associated with granular corneal dystrophy type 1 reduces the proteolytic susceptibility through local structural stabilization

Underhaug, Jarl; Koldsø, Heidi; Runager, Kasper; Nielsen, Jakob T.; Sørensen, Charlotte Mehlin; Kristensen, Torsten Nygaard; Otzen, Daniel E.; Karring, Henrik; Malmendal, Anders; Schiøtt, Birgit; Enghild, Jan J.; Nielsen, Niels Chr.

doi:10.1016/j.bbapap.2013.10.008

Cited by 37 publications

(65 citation statements)

References 45 publications

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“…Missense mutations in the fourth FAS1 domain lead to dystrophic corneal deposition by altering TGFBI structure, stability and subsequent protein processing or by affecting TGFBI turnover and fibrillation rates, causing increased aggregation 2. Specifically, a proteolytic cleavage site has been shown to be between the wild-type Arg557 and Leu558 residues in the core of the fourth FAS1 domain 22. Thus, the p.(Leu558Pro) mutation may result in a mutant TGFBI protein that is significantly less susceptible to proteolysis, disrupting the normal degradation and turnover of corneal TGFBI, as demonstrated for the p.(Arg555Trp) mutation, leading to dystrophic corneal deposition 22.…”

Section: Discussionmentioning

confidence: 99%

Variant lattice corneal dystrophy associated with compound heterozygous mutations in theTGFBIgene

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Variant lattice corneal dystrophy associated with compound heterozygous mutations in theTGFBIgene

et al. 2016

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“…These proteins share a similar conformation distinguished by a structural element in the middle and extensions at both sides (Extended Data Figs 3f, g, 8). The structural element comprises a long α -helix in L RC 4 and L RC 5 and a FAS1 29,33 domain in L RC 6 (Extended Data Figs 3f, g, 8). The long α -helix of L RC 4 and L RC 5 spans one α -subunit of the core trimer (Extended Data Fig.…”

Section: Rod-core Linker Proteinsmentioning

confidence: 99%

Structure of phycobilisome from the red alga Griffithsia pacifica

Zhang

Liu

et al. 2017

Nature

204

199

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The cyanobacteria and red algae are two important groups of photosynthetic organisms that share a light-harvesting antenna known as the phycobilisome (PBS) [1][2][3][4] . PBSs are among the largest protein complexes in the living world and consist of phycobiliproteins (PBPs), including phycocyanin, phycoerythrin and allophycocyanin (APC), and linker proteins . Two subunits of PBPs, the α -and β -subunits, form an α β heterodimer that is conventionally called an (α β ) monomer. The monomer is then assembled into an (α β ) 3 trimer, the basic unit of PBS hierarchical assembly. The trimers of various PBPs are organized into a highly ordered supramolecular complex with the help of the linker proteins 1,5,6 . Four morphological types of PBS 1 are known: hemidiscoidal 7 , hemiellipsoidal 8 , block-type 9 and bundle-type 10. The hemidiscoidal PBS contains a central core surrounded by peripheral rods 1,11,12 . The chromophores in hemidiscoidal PBS are arranged in such a way that a photon absorbed by a chromophore in the peripheral rods is rapidly funnelled to chromophores in the core 13 and eventually to the terminal emitters (the core-membrane linker protein (L CM ) [14][15][16] or allophycocyanin D (ApcD) 17,18 ). The terminal emitters then transfer the energy to photosynthetic reaction centres 16,[19][20][21][22][23] . Currently, the mechanism of PBS assembly is poorly understood and the energy transfer routes within PBSs are not well defined. Although 3D structures of some individual PBPs have been reported (reviewed in refs 2, 3), the structures of most linker proteins are unknown and the complete structure of a PBS has not been published, to our knowledge. Here we report the cryo-electron microscopy (cryo-EM) structure of a PBS from the red alga Griffithsia pacifica at a resolution of 3.5 Å, which reveals details of the PBS architecture. Overall structureThe PBS from G. pacifica was purified and its intactness confirmed by its protein composition and spectroscopic features (Extended Data Fig. 1a-f). We reconstructed a 3D structure of the intact PBS by single particle cryo-EM with an overall resolution of 3.5 Å (Extended Data Table 1). Applying individual local masks improved the resolutions of local maps to 3.4-4.3 Å (Extended Data Fig. 2g). The PBS is one of the largest supramolecular complexes that has been reported, with a calculated molecular mass of approximately 16.8 megadaltons. The overall appearance is block-type 9 with twofold symmetry oriented perpendicularly to the thylakoid membranes (Fig. 1a-c and Extended Data Figs 1g-l, 3a-d). This PBS is larger than the hemiellipsoidal PBS isolated from Porphyridium cruentum8 and has dimensions of approximately 680 Å length, 390 Å height, and 450 Å thickness (Fig. 1a-c).The PBS contains a triangular core with the top cylinder B (formed by two APC trimers) sitting above two basal cylinders A and A′ (each formed by three APC trimers) surrounded by peripheral rods arranged in a staggered fashion (Fig. 1a-c and Extended Data Fig. 3c-e). In addition to the core and ...

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“…Protein misfolding may promote cellular degeneration and cell death (Kopito, 2000;Estey et al, 2010;Underhaug et al, 2013, Viiri et al, 2013. All cells have special surveillance systems to control steady-state of the folding and clearance of proteins.…”

Section: Discussionmentioning

confidence: 99%

A novel proteotoxic stress‐associated mechanism for macular corneal dystrophy

Szalai

Smędowski²,

Wylęgała³

et al. 2014

Acta Ophthalmologica

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Summary. Macular corneal dystrophy is a rare autosomal recessive eye disease affecting primarily the corneal stroma. Abnormal accumulation of proteoglycan aggregates has been observed intra-and extracellularly in the stromal layer. In addition to the stromal keratocytes and corneal lamellae, deposits are also present in the basal epithelial cells, endothelial cells and Descemet's membrane. Misfolding of proteins has a tendency to gather into aggregating deposits. We studied interaction of molecular chaperones and proteasomal clearance in macular dystrophy human samples and in human corneal HCE-2 epithelial cells. Seven cases of macular corneal dystrophy and four normal corneal buttons collected during corneal transplantation were examined for their expression patterns of heat shock protein 70, ubiquitin protein conjugates and SQSTM1/p62. In response to proteasome inhibition the same proteins were analyzed by western blotting. Slitlamp examination, in vivo confocal cornea microscopy and transmission electron microscopy were used for morphological analyses. Heat shock protein 70, ubiquitin protein conjugates and SQSTM1/p62 were upregulated in both the basal corneal epithelial cells and the stromal keratocytes in macular corneal dystrophy samples that coincided with an increased expression of the same molecules under proteasome inhibition in the HCE-2 cells in vitro. We propose a novel regulatory mechanism that connects the molecular chaperone and proteasomal clearance system in the pathogenesis of macular corneal dystrophy.

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Mutation in transforming growth factor beta induced protein associated with granular corneal dystrophy type 1 reduces the proteolytic susceptibility through local structural stabilization

Cited by 37 publications

References 45 publications

Variant lattice corneal dystrophy associated with compound heterozygous mutations in theTGFBIgene

Variant lattice corneal dystrophy associated with compound heterozygous mutations in theTGFBIgene

Structure of phycobilisome from the red alga Griffithsia pacifica

A novel proteotoxic stress‐associated mechanism for macular corneal dystrophy

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