Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: Relevance to diseases of the nervous system

Kahlem, Pascal; Terré, C.; Green, H.; Djian, Philippe

doi:10.1073/pnas.93.25.14580

Cited by 185 publications

(137 citation statements)

References 44 publications

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“…Interestingly, the A-type repeats display the highest homology to HRNR (8), an epidermal protein recently shown to be a component of cornified cell envelopes (28). A-type repeats of FLG2 and HRNR both contain high percentages of Gln (15 and 9.4%, respectively), which is a key amino acid for transglutaminase-mediated cross-linking to the cornified envelope (53,54), suggesting that the A-type repeat domain is cross-linked to these corneocyte structures.…”

Section: Discussionmentioning

confidence: 99%

Deimination of Human Filaggrin-2 Promotes Its Proteolysis by Calpain 1

Hsu

Henry

Raymond

et al. 2011

Journal of Biological Chemistry

113

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Filaggrin-2 (FLG2), a member of the S100-fused type protein family, shares numerous features with filaggrin (FLG), a key protein implicated in the epidermal barrier functions. Both display a related structural organization, an identical pattern of expression and localization in human epidermis, and proteolytic processing of a large precursor. Here, we tested whether FLG2 was a substrate of calpain 1, a calcium-dependent protease directly involved in FLG catabolism. In addition, deimination being critical for FLG degradation, we analyzed whether FLG2 deimination interfered with its proteolytic processing. With this aim, we first produced a recombinant form of FLG2 corresponding to subunits B7 to B10 fused to a COOH-terminal His tag. Incubation with calpain 1 in the presence of calcium induced a rapid degradation of the recombinant protein and the production of several peptides, as shown by Coomassie Blue-stained gels and Western blotting with anti-FLG2 or anti-His antibodies. MALDI-TOF mass spectrometry confirmed this result and further evidenced the production of non-immunoreactive smaller peptides. The degradation was not observed when a calpain 1-specific inhibitor was added. The calpain cleavage sites identified by Edman degradation were regularly present in the B-type repeats of FLG2. Moreover, immunohistochemical analysis of normal human skin revealed colocalization of FLG2 and calpain 1 in the upper epidermis. Finally, the FLG2 deiminated by human peptidylarginine deiminases was shown to be more susceptible to calpain 1 than the unmodified protein. Altogether, these data demonstrate that calpain 1 is essential for the proteolytic processing of FLG2 and that deimination accelerates this process.In the epidermis, the program of keratinocyte terminal differentiation is an oriented process during which cells of the basal layer undergo a series of metabolic and structural changes throughout their migration to the surface of the tissue. The stratum corneum, the outermost layer of the epidermis, is formed by the stacking of so-called corneocytes, the end products of the process. The stratum corneum functions as an effective barrier between the body and its outside environment, limiting skin dehydration and preventing the penetration of outside pathogens, UV radiation, and exogenous chemicals. It also contributes to mechanical protection of the body. So that this function can be achieved, peculiar structures are formed, such as the cornified cell envelope, a resistant and insoluble protein shell that replaces the plasma membrane, and the intracorneocyte fibrous matrix made by the aggregation of keratin intermediate filaments.

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Section: Discussionmentioning

confidence: 99%

Deimination of Human Filaggrin-2 Promotes Its Proteolysis by Calpain 1

Hsu

Henry

Raymond

et al. 2011

Journal of Biological Chemistry

113

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“…Our studies of glutamine repeats in synthetic peptides made by solid-phase synthesis showed that increasing the number of consecutive glutamine residues led to increased reactivity of each residue in a transglutaminase-catalyzed reaction; ultimately as many as 80% of the total glutamine residues participated in the reaction (9). Experiments by others showed that the addition of polyQ to the protein GST greatly increased its reactivity as a transglutaminase substrate (10).…”

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confidence: 85%

Oligomeric and polymeric aggregates formed by proteins containing expanded polyglutamine

Iuchi

Hoffner

Verbeke

et al. 2003

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

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Neurological diseases resulting from proteins containing expanded polyglutamine (polyQ) are characteristically associated with insoluble neuronal inclusions, usually intranuclear, and neuronal death. We describe here oligomeric and polymeric aggregates formed in cells by expanded polyQ. These aggregates are not dissociated by concentrated formic acid, an extremely effective solvent for otherwise insoluble proteins. Perinuclear inclusions formed in cultured cells by expanded polyQ can be completely dissolved in concentrated formic acid, but a soluble protein oligomer containing the expanded polyQ and released by the formic acid is not dissociated to monomer. In Huntington's disease, a formic acid-resistant oligomer is present in cerebral cortex, but not in cerebellum. Cortical nuclei contain a polymeric aggregate of expanded polyQ that is insoluble in formic acid, does not enter polyacrylamide gels, but is retained on filters. This finding shows that the process of polymerization is more advanced in the cerebral cortex than in cultured cells. The resistance of oligomer and polymer to formic acid suggests the participation of covalent bonds in their stabilization.

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“…The devastating Altzheimer's disease might be derived from the crosslinking of the neurofilaments, microtubule-associated tau proteins, or amyloid β proteins (Selkoe et al, 1982;Miller and Anderton, 1986;Lorand, 1996). The gene products with polyglutamine tracts whose length is determined by the number of CAG repeats could be the putative substrates for TGase, associated with Huntington's disease, spinocerebellar ataxia type I, dentarubral-phallidoluysian atrophy, spinobulbar muscular atrophy and spinocerebeller ataxia type 3 (Cariello et al, 1996;Kahlem et al, 1996). The midkine, a highly basic heparin-binding cytokine, dimerized by a TGase can stabilize the growth factor, endowing its neurite-promoting activity amplification (Mahoney et al, 1986).…”

Section: Five Different Types Of Tgases From the Mammalian 181mentioning

confidence: 99%

Isolation and characterization of brain-specific transglutaminases from rat

Kwak

Kim²,

Kim³

et al. 1998

Exp Mol Med

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The relevance of transglutaminases with neural function and several disorders has been emphasized recently. Especially, many polypeptides associated with neurodegenerative diseases are suggested to be putative transglutaminase substrates such as amyloid protein of Altzheimer's disease, microtubule-associated proteins and neurofilaments, etc. In addition, the CAG repeated gene products with probable polyglutamine tract, putative transglutami-nase substrates, were identified in several neuro-degenerative disorders. However, the identity of the brain transglutaminase has not been confirmed, because of enzymic stability and low activity. In the present experiment, we have isolated brain-specific transglutaminases, designated as TGase NI and TGase NII, which are different from other types of transglutaminases in respects of molecular weights (mw. 45 kDa, 29 kDa respectively), substrate affinity, elution profile on ion-exchange chromatography, sensitivity to proteases and ethanol, and immuno-logical properties. The enzymes were localized specifically in the brain tissues but not in the liver tissue. And neural cells such as pheochromocytoma cell, glioma cell, primary neuronal and glial cells were shown to be enriched with TGase NI and TGase NII. The possible biological roles of the enzymes were discussed not only on the aspect of crosslinking activity but also of signal transducing capacity of the enzyme in the brain. K e y w o r d s : TGase NI, TGaase NII, brain, rat, localization

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Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: Relevance to diseases of the nervous system

Cited by 185 publications

References 44 publications

Deimination of Human Filaggrin-2 Promotes Its Proteolysis by Calpain 1

Deimination of Human Filaggrin-2 Promotes Its Proteolysis by Calpain 1

Oligomeric and polymeric aggregates formed by proteins containing expanded polyglutamine

Isolation and characterization of brain-specific transglutaminases from rat

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