G76E Substitution in Type I Collagen Is the First Nonlethal Glutamic Acid Substitution in the α1(I) Chain and Alters Folding of the N-terminal End of the Helix

Cabral, Wayne A.; Chernoff, Edith J.; Marini, Joan C.

doi:10.1006/mgme.2001.3155

Cited by 8 publications

(5 citation statements)

References 28 publications

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“…These collagenases cleave the collagens types I, II and III specifically at a single site (Gly 775 –Leu/Ile 776 ) within each α chain of the triple helical collagen molecule [ 37 ]. The exact cleavage position in the R789C protein is yet to be identified, but it is attractive to speculate that the mutation in close proximity of the well-known MMP cleavage site facilitates cleavage due to local unfolding [ 38 , 39 , 40 ]. The fact that pretreatment of the cells with the MMP inhibitor GM6001 abrogated the processing further supports the notion that MMPs are responsible for the cleavage.…”

Section: Discussionmentioning

confidence: 99%

Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival

Chakkalakal

Heilig

Baumann

et al. 2018

IJMS

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Inherited point mutations in collagen II in humans affecting mainly cartilage are broadly classified as chondrodysplasias. Most mutations occur in the glycine (Gly) of the Gly-X-Y repeats leading to destabilization of the triple helix. Arginine to cysteine substitutions that occur at either the X or Y position within the Gly-X-Y cause different phenotypes like Stickler syndrome and congenital spondyloepiphyseal dysplasia (SEDC). We investigated the consequences of arginine to cysteine substitutions (X or Y position within the Gly-X-Y) towards the N and C terminus of the triple helix. Protein expression and its secretion trafficking were analyzed. Substitutions R75C, R134C and R704C did not alter the thermal stability with respect to wild type; R740C and R789C proteins displayed significantly reduced melting temperatures (Tm) affecting thermal stability. Additionally, R740C and R789C were susceptible to proteases; in cell culture, R789C protein was further cleaved by matrix metalloproteinases (MMPs) resulting in expression of only a truncated fragment affecting its secretion and intracellular retention. Retention of misfolded R740C and R789C proteins triggered an ER stress response leading to apoptosis of the expressing cells. Arginine to cysteine mutations towards the C-terminus of the triple helix had a deleterious effect, whereas mutations towards the N-terminus of the triple helix (R75C and R134C) and R704C had less impact.

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Section: Discussionmentioning

confidence: 99%

Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival

Chakkalakal

Heilig

Baumann

et al. 2018

IJMS

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“…In some cases, phenotypes are different, although the same mutations are identified. The substitution of glutamic acid for glycine in COL1A1 gene is a rare event, with only two previous reports in the literature 18,19 . Two Gly76Glu mutations and one Gly88Glu mutation have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…The substitution of glutamic acid for glycine in COL1A1 gene is a rare event, with only two previous reports in the literature. 18,19 Two Gly76Glu mutations and one Gly88Glu mutation have been reported. One Gly76Glu mutation resulted in OI type III.…”

Section: Discussionmentioning

confidence: 99%

Mutations in type I collagen genes in Japanese osteogenesis imperfecta patients

Kataoka

Ogura

Hasegawa

et al. 2007

Pediatrics International

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“…Defects in type I collagen have been implicated in Osteogenesis imperfecta (OI), a heritable disorder of bone formation characterized by osteopenia and bone fragility, with seven classes or types of the disease based on clinical presentation and bone architecture [8,9] . Some OI is caused by mutations in one of the type I collagen genes resulting in the substitution of glycine in the collagen a chain by amino acids with bulkier side chains [10][11][12][13][14][15] . Collagen-like model peptides have proven to be a useful tool to study how glycine substitutions in collagen a chains affects the hierarchical assembly of collagen a chain into triple helical collagen molecules [16][17][18] as well as to predict clinical lethality of OI with different glycine substitutions.…”

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confidence: 99%

Hierarchical Assembly of Collagen‐Like Peptides in vitro Provides Structural Causes of Osteogenesis Imperfecta

Huang¹,

Cebe²,

Kaplan³

2009

Macromol. Rapid Commun.

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Collagen type I peptides, representative of native to disease states for the bone disease, Osteogenesis imperfecta, were studied with regard to self-assembly into triple helices and liquid crystalline mesophases. The purpose of the study was to establish insight into collagen mutations in terms of propagation of single chain defects up the scale of materials hierarchy, toward solid state fibril assemblies formed from collagen. Studies carried out in vitro demonstrated the value of this approach in establishing in vitro disease models, as the degree of collagen disruption could be recapitulated by the point mutations to show major impact on macroscopic features. Fourier transform infrared spectroscopy, circular dichroism, atomic force microscopy and optical ellipsometry were used to assess the structural and morphological changes at the various length scales post assembly. The results demonstrated that glycine to alanine to aspartic acid single substitutions in the collagen peptides progressively disrupted normal assembly, reflected in lower thermal stability, loss of triple helical structure and loss of mesophase formation. This approach can provide a basis upon which to study collagen biomaterial templates for controlled hydroxyapatite formation and changes in cell signaling related to bone remodeling, related to the severity of the disease.

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G76E Substitution in Type I Collagen Is the First Nonlethal Glutamic Acid Substitution in the α1(I) Chain and Alters Folding of the N-terminal End of the Helix

Cited by 8 publications

References 28 publications

Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival

Impact of Arginine to Cysteine Mutations in Collagen II on Protein Secretion and Cell Survival

Mutations in type I collagen genes in Japanese osteogenesis imperfecta patients

Hierarchical Assembly of Collagen‐Like Peptides in vitro Provides Structural Causes of Osteogenesis Imperfecta

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