Villin-1 is a 92.5 kDa tissue-specific actin-binding protein associated with the actin core bundle of the brush border. Villin-1 is encoded by the VIL1 gene. Villin-1 contains multiple gelsolin-like domains capped by a small (8.5 kDa) "headpiece" at the C-terminus consisting of a fast and independently folding three-helix bundle that is stabilized by hydrophobic interactions. The headpiece domain is a commonly studied protein in molecular dynamics due to its small size and fast folding kinetics and short primary sequence.
Expression Villin-1 is an actin binding protein expressed mainly in the brush border of the epithelium in vertebrates but sometimes it is ubiquitously expressed in protists and plants. Villin is found localized in the microvilli of the brush border of the epithelium lining of the gut and renal tubules in vertebrates.
Structure Villin-1 consists of seven domains: six homologous domains that form the N-terminal core and a seventh domain that forms the C-terminal headpiece (cap). The core comprises approximately 150 amino acid residues organized into six repeated segments, while the C-terminal headpiece is an 87-residue hydrophobic region. Villin contains three phosphatidylinositol 4,5-bisphosphate (PIP2) binding sites, one in the headpiece and two in the core domain. The C-terminal headpiece (HP67) is a compact, independently folded 70-amino-acid domain that contains the principal F-actin-binding site. Residues K38, E39, K65, K70–K73, G74, L75, and F76 surround a hydrophobic core and are believed to contribute to F-actin binding. Residues E39 and K70 form a buried salt bridge linking the N- and C-terminal regions of the headpiece, which appears to stabilize the conformation required for actin binding, as disruption of this interaction abolishes binding. Residue W64 forms a conserved hydrophobic cap that is characteristic of the villin family, beneath which lies a crown of alternating positively and negatively charged residues. The C-terminal subdomain of the headpiece, designated VHP35, is stabilized in part by a buried cluster of three phenylalanine residues. Its small size and high α-helical content promote rapid folding, a property that has been confirmed experimentally. The related Arabidopsis thaliana villin-4 C-terminal construct VHP76 exhibits increased affinity for F-actin at elevated Ca2+ concentrations, further supporting the conserved role of the headpiece in actin binding. Overall, the headpiece adopts a simple topology of three α-helices surrounding a tightly packed hydrophobic core. Villin-1 also undergoes post-translational modification by tyrosine phosphorylation, and can form dimers through a dimerization site located near the amino terminus of the protein.
Function Villin-1 is believed to function in the bundling, nucleation, capping and severing of actin filaments. In vertebrates, villin proteins help to support the microfilaments of the microvilli of the brush border. However, knockout mice appear to show ultra-structurally normal microvilli reminding us that the function of villin is not definitively known; it may play a role in cell plasticity through F-actin severing. The six-repeat villin core is responsible for Ca2+ actin severing while the headpiece is responsible for actin crosslinking and bundling (Ca independent). Villin is postulated to be the controlling protein for Ca2+ induced actin severing in the brush border. Ca2+ inhibits proteolytic cleavage of the domains of the 6 N-terminal core which inhibits actin severing. In normal mice raising Ca2+ levels induces the severing of actin by villin, whereas in villin knockout mice this activity does not occur in response to heightened Ca2+ levels. In the presence of low concentrations of Ca2+ the villin headpiece functions to bundle actin filaments whereas in the presence of high Ca2+ concentrations the N-terminal caps and severs these filaments. The association of PIP2 with villin inhibits the actin capping and severing action and increases actin binding at the headpiece region, possibly through structural changes in the protein. PIP2 increases actin bundling not only by decreasing the severing action of villin but also through dissociating capping proteins, releasing actin monomers from sequestering proteins and stimulating actin nucleation and cross linking.
Degradation and regulation Currently, it is theorized the regulation of plant villins are caused by degradation via the binding protein auxin, which targets the headpiece domain (VHP).
Role in intestinal and liver disease Villin-1 acts as a critical determinant of intestinal epithelial survival and barrier integrity. While classically defined by its cytoskeletal function (actin binding, caping and severing), it also serves as an epithelial cell-specific anti-apoptotic protein.
Inflammatory bowel disease (IBD) In IBD (conditions such as Crohn's disease and ulcerative colitis), villin-1 expression is downregulated in the inflamed gut mucosa. This reduction correlates with the loss of tight junction proteins and Notch-1 signaling, leading to increased intestinal permeability ("leaky gut") and heightened sensitivity to cytokine-induced apoptosis.
Biomarker for gut barrier failure Serum villin-1 was identified as a novel, non-invasive biomarker for gut barrier damage in patients with acutely decompensated (AD) cirrhosis and acute-on-chronic liver failure (ACLF). Serum villin-1 levels follow a gradient of severity, rising significantly in patients transitioning from stable decompensation to ACLF. High serum concentrations are independently associated with systemic inflammation and high 90-day mortality rates. Conversely, tissue biopsies from these patients show a depletion of Villin-1 in the duodenal mucosa, confirming an inverse relationship between tissue integrity and serum levels during severe disease states.
See also Supervillin
References
Further reading
External links Villin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
