Abstract
Gastrokine 1 (GKN1) is a 18 kDa stomach protein highly expressed in normal gastric tissue but absent in gastric cancer. GKN1 plays its major role in maintaining gastric mucosal integrity. Because of the presence in its central region of a BRICHOS domain, GKN1 is characterized by multifunctional properties since it interacts and regulates the activity of several proteins. The BRICHOS domain consists of about 100 amino acids and has been found in protein families often associated with major human diseases like familial British and Danish dementia (BRI2) or respiratory distress syndrome (surfactant protein C) (SP-C), both associated with amyloid formation. It has been shown that BRICHOS is a chaperon domain that has the property of binding precursor protein regions with high β-sheet tendencies, thereby preventing them from amyloid formation. Like the BRICHOS domains from BRI2 and SP-C precursor (proSP-C), also GKN1 is able to prevent fibrils formation of amyloid-beta peptide (Aβ) and to interact with the C-terminal region of APP thus hindering the γ-secretase proteolytic sites. Indeed, amyloid is of great medical importance since it originates in several major fatal diseases such as Alzheimer, Parkinson and diabetes mellitus. The results collected until now on the BRICHOS properties of GKN1 and those from other BRICHOS suggest that the different amyloids recognized by BRICHOS should contain similar structural elements therefore, the BRICHOS domain represents a potential powerfull tool for therapeutic approaches against amyloid associated diseases. Abbreviations: AD, Alzheimer disease; Aβ, amyloid-beta peptide; APP, amyloid precursor protein; CTFs, APP C-Terminal Fragments; GC, gastric cancer; DAPT, N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; DMSO, dimethyl sulfoxyde; GC, gastric cancer; GKN1, gastrokine 1; flGKN1, full-lenght GKN1; MS, mass spectrometry; rGKN1, recombinant GKN1; SPR, surface plasma resonance; TM, transmembrane; TMpred, transmembrane prediction.
Highlights
Gastrokine[1] (GKN1), a 18 kDa protein known as antrum mucosal protein (AMP-18)[1], is highly expressed in the gastric mucosa of many mammals species[1,2]
The recombinant BRICHOS domains of these proteins possess a chaperon-like function by precluding fibrils formation of amyloid-beta peptides (1-40) and (142)[14,15], the products associated to the Alzheimer disease (AD) that are liberated by the amyloid precursor protein (APP)[16]
Because C-terminal Fragments (CTFs), C83 and C99 are released during APP processing by α- and β-secretases, respectively, these results indicates that the interaction of Gastrokine 1 (GKN1) with APP protects APP from γ-secretase
Summary
Gastrokine[1] (GKN1), a 18 kDa protein known as antrum mucosal protein (AMP-18)[1], is highly expressed in the gastric mucosa of many mammals species[1,2]. Edman’s degradation performed on native human GKN1 confirmed the assumption and showed that the protein contains in its N-terminal region a 20 amino acids extracellular signal peptide[3] (Figure 1). Beside its role in gastric mucosal protection, GKN1 plays other important additional functions correlated to the presence in its central region of a conserved BRICHOS domain of near 100 amino acids that has been found in proteins characterized by several biological functions and disease associations (Fig. 1)[12].
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