Site‐specific transamidation and deamidation of the small heat‐shock protein Hsp20 by tissue transglutaminase

Boros, Sándor; Åhrman, Emma; Wunderink, Lisa; Kamps, Bram; Jong, WW de; Boelens, WC; Emanuelsson, Cecilia

doi:10.1002/prot.20837

Cited by 24 publications

(24 citation statements)

References 42 publications

(74 reference statements)

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“…However, because the higher molecular mass forms detected here are present after denaturing electrophoresis, they must be formed by covalent cross-linking of multiple monomers to themselves (the molecular mass of the major forms in mouse suggests a trimer) or other proteins. In amyloid plaques, HspB1 is cross-linked into large multi-species protein aggregates by tissue transglutaminase (37). HspB1 has multiple glutamine and lysine residues, making it a potential substrate for the abundant transglutaminases in the upper epidermis that become active developmentally when HspB1 monomer is lost.…”

Section: Discussionmentioning

confidence: 99%

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

O'Shaughnessy

Welti

Cooke

et al. 2007

Journal of Biological Chemistry

117

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AKT activity has been reported in the epidermis associated with keratinocyte survival and differentiation. We show in developing skin that Akt activity associates first with post-proliferative, para-basal keratinocytes and later with terminally differentiated keratinocytes that are forming the fetal stratum corneum. In adult epidermis the dominant Akt activity is in these highly differentiated granular keratinocytes, involved in stratum corneum assembly. Stratum corneum is crucial for protective barrier activity, and its formation involves complex and poorly understood processes such as nuclear dissolution, keratin filament aggregation, and assembly of a multiprotein cell cornified envelope. A key protein in these processes is filaggrin. We show that one target of Akt in granular keratinocytes is HspB1 (heat shock protein 27). Loss of epidermal HspB1 caused hyperkeratinization and misprocessing of filaggrin. Akt-mediated HspB1 phosphorylation promotes a transient interaction with filaggrin and intracellular redistribution of HspB1. This is the first demonstration of a specific interaction between HspB1 and a stratum corneum protein and indicates that HspB1 has chaperone activity during stratum corneum formation. This work demonstrates a new role for Akt in epidermis.The epidermis is the primary environmental barrier, protecting from infection, allergens, and damage from UV radiation. The major constituent of this epidermal barrier is the terminally differentiated, anuclear keratinocyte. This structure is bounded by a cornified envelope, an elaborate, cross-linked protein structure covalently bound to hydrophobic lipid externally and aggregated keratin internally (1). Formation of this structure is poorly understood.The complexity of keratinocyte terminal differentiation and the importance of precisely timed and compartmentalized processing is illustrated by the maturation of the stratum corneum protein filaggrin. Filaggrin is synthesized as a high molecular mass precursor comprising multiple subunits that are sequentially processed and modified in temporally and spatially regulated steps by diverse proteases and enzymes to produce mature filaggrin subunits. Mature filaggrin is thought to be important in the aggregation and collapse of the keratin network leading to flattening of the keratinocyte and the destruction of the nucleus in granular layer (terminally differentiating) keratinocytes (2). Filaggrin is also incorporated into the cornified envelope (2). Premature or aberrant filaggrin processing can be catastrophic, leading to disruption of cornified envelope integrity and skin barrier function (3-5) and is far more damaging than reduced filaggrin levels that, in contrast, lead only to mild skin defects (6).Possible regulators of protein processing and trafficking during terminal differentiation are heat shock proteins (Hsps). 2Hsps have diverse roles as cellular chaperones, anti-apoptotic factors, stress-protective proteins, and cytoskeletal stabilizers (7,8). Human HspB1 (Hsp27) (9 -11) and the mouse HspB1...

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Section: Discussionmentioning

confidence: 99%

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

O'Shaughnessy

Welti

Cooke

et al. 2007

Journal of Biological Chemistry

117

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“…At best, deamination reactions were believed to be favored only under certain conditions such as lower than physiological pH [27]. It was rarely, if at all, considered that TG2 might actually deaminate a protein even when conditions were permissive for transamidation until a study showed that a glutamine residue in Hsp20 was specifically deaminated while other glutamine residues were transamidated [28]. Further studies showed that specific deamination is observed in other proteins as well [29], and the number of reports examining the structural features of substrates that favor deamination over transamidation is growing [29, 30].…”

Section: Tg2: Transamidating/deaminating Functionmentioning

confidence: 99%

Transglutaminase 2: A molecular Swiss army knife

Gundemir

Colak

Tucholski

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

212

356

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Transglutaminase 2 (TG2) is the most widely distributed member of the transglutaminase family with almost all cell types in the body expressing TG2 to varying extents. In addition to being widely expressed, TG2 is an extremely versatile protein exhibiting transamidating, protein disulphide isomerase and guanine and adenine nucleotide binding and hydrolyzing activities. TG2 can also act as a protein scaffold or linker. This unique protein also undergoes extreme conformational changes and exhibits localization diversity. Being mainly a cytosolic protein; it is also found in the nucleus, associated with the cell membrane (inner and outer side) and with the mitochondria, and also in the extracellular matrix. These different activities, conformations and localization need to be carefully considered while assessing the role of TG2 in physiological and pathological processes. For example, it is becoming evident that the role of TG2 in cell death processes is dependent upon the cell type, stimuli, subcellular localization and conformational state of the protein. In this review we discuss in depth the conformational and functional diversity of TG2 in the context of its role in numerous cellular processes. In particular, we have highlighted how differential localization, conformation and activities of TG2 may distinctly mediate cell death processes.

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“…The deamidation reaction, which is favored with poor substrates, low TG concentrations, and low pH (Stamnaes et al, 2008), has a certain degree of substrate specificity. For example, TG2 caused deamidation of Gln66 and transamidation of Gln31 to Lys162 in Hsp20 protein (Boros et al, 2006). The deamidating function of TG2 received much attention when it was reported to catalyze deamidation of peptides derived from the wheat protein gliadin, causing them to become dominant epitopes for activating T cells associated with the pathogenesis of celiac disease (Shan et al, 2002; Sollid and Jabri, 2005).…”

Section: Enzymatic and Nonenzymatic Activities Of Tg2mentioning

confidence: 99%

Cellular Functions of Tissue Transglutaminase

Nurminskaya

Belkin

2012

International Review of Cell and Molecular Biology

216

255

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Transglutaminase 2 (TG2 or tissue transglutaminase) is a highly complex multifunctional protein that acts as transglutaminase, GTPase/ATPase, protein disulfide isomerase, and protein kinase. Moreover, TG2 has many well-documented nonenzymatic functions that are based on its noncovalent interactions with multiple cellular proteins. A vast array of biochemical activities of TG2 accounts for its involvement in a variety of cellular processes, including adhesion, migration, growth, survival, apoptosis, differentiation, and extracellular matrix organization. In turn, the impact of TG2 on these processes implicates this protein in various physiological responses and pathological states, contributing to wound healing, inflammation, autoimmunity, neurodegeneration, vascular remodeling, tumor growth and metastasis, and tissue fibrosis. TG2 is ubiquitously expressed and is particularly abundant in endothelial cells, fibroblasts, osteoblasts, monocytes/macrophages, and smooth muscle cells. The protein is localized in multiple cellular compartments, including the nucleus, cytosol, mitochondria, endolysosomes, plasma membrane, and cell surface and extracellular matrix, where Ca2+, nucleotides, nitric oxide, reactive oxygen species, membrane lipids, and distinct protein–protein interactions in the local microenvironment jointly regulate its activities. In this review, we discuss the complex biochemical activities and molecular interactions of TG2 in the context of diverse subcellular compartments and evaluate its wide ranging and cell type-specific biological functions and their regulation.

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Site‐specific transamidation and deamidation of the small heat‐shock protein Hsp20 by tissue transglutaminase

Cited by 24 publications

References 42 publications

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

AKT-dependent HspB1 (Hsp27) Activity in Epidermal Differentiation

Transglutaminase 2: A molecular Swiss army knife

Cellular Functions of Tissue Transglutaminase

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