Reinforcement of the Cornified Envelope

Stable Identifier
Reaction [omitted]
Homo sapiens
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The inital scaffold of the cornified envelope (CE) is reinforced by the inclusion of loricrin (LOR) and small proline-rich proteins (SPRs), which together comprise about 75% of the total mass of the CE. Other proteins include filaggrin (FLG) (8%), elafin (6%), cystatin A (5%), involucrin (IVL) and keratin intermediate filaments (KIFs) (about 2% each) (Steinert & Marekov 1995). Other minor proteins include repetin (RPTN), trichohyalin (TCHH) and elafin (PI3) (Steinert & Marekov 1997, Steinert et al. 1998).

LOR is poorly soluble in vivo, while SPRs are very soluble. Both are preferred substrates of cytosolic transglutaminase-3 (TGM3) (Candi et al. 1999, Steinert et al. 1999, Tarcsa et al. 1999), which suggests that TGM3 may cross-link LOR and SPRs to create soluble complexes that are more easily translocated to the cell periphery (Kalinin et al. 2002). These cross-linked oligomers are good substrates for TGM1 (Candi et al. 1999, Steinert et al. 1999) which may link the LOR-SPR complexes to the CE scaffold. LOR can also be crosslinked by TGM5 (Candi et al. 2001). SPR content varies in epithelia from different body sites and increasing SPR content correlates with mechanical requirements of the tissue (Steinert et al. 1998). In humans LOR is initially deposited in the granular layer of the epidermis in keratohyalin granules, intermixed with profilaggrin (Yoneda & Steinert 1993). These are encoded in a linked 'Epidermal Differentiation Complex.' (Kypriotou et al. 2012, Niehues et al. 2016).

As the main component of the CE (Steinert & Marekov 1995), LOR is thought to function as the main reinforcement protein. LOR proteins are extensively crosslinked through isopeptide bonds but also crosslinked to SPRs, which may function as bridging proteins between LOR molecules (Candi et al. 2005). LOR can also form crosslinks with keratin and filaggrin (Steinert & Marekov 1995). CE crosslinking involves TGM1, TGM3 and TGM5 (Lorand & Graham 2003). The type-II keratin chains (K1, K2e and K5) are crosslinked at a specific Lys residue that is located in a conserved region of the V1 subdomain of the head domain (Steinert & Marekov 1995). IVL can be crosslinked by TGM1, which preferentially crosslinks Gln495 and Gln496 (Simon & Green 1998). In vitro, LOR is a substrate for TGM1-3 and 5 (Candi et al. 1995). In the epidermis, TGM1, TGM5 and TGM3 are believed to crosslink LOR sequentially; an initial attachment by TGM1 and 5 forms interchain crosslinks followed by a compaction process that involves TGM3 (Candi et al. 2005). SPRs are also TGM substrates, particularly TGM3 (Candi et al. 1999, Tarcsa et al. 1998, Steinert et al. 1999).

FLG binds KIFs, aggregating them into tight bundles. As a component of the CE, FLG 'glues' KIFs to the CE and coordinates the structure of cornifying cells (Steinert & Marekov 1995, Candi et al. 2005).
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