Villin-1

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.^[6] Villin is found localized in the microvilli of the brush border of the epithelium lining of the gut and renal tubules in vertebrates.^[7]

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).^[5] The core comprises approximately 150 amino acid residues organized into six repeated segments, while the C-terminal headpiece is an 87-residue hydrophobic region.^[3] Villin contains three phosphatidylinositol 4,5-bisphosphate (PIP₂) binding sites, one in the headpiece and two in the core domain.^[7]

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.^[7]

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,^[8] and can form dimers through a dimerization site located near the amino terminus of the protein.^[9]

Villin-1 is believed to function in the bundling, nucleation, capping and severing of actin filaments.^[3] 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.^[7] 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.^[5] 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.^[10] 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.^[3] 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.^[5]

Currently, it is theorized the regulation of plant villins are caused by degradation via the binding protein auxin, which targets the headpiece domain (VHP).

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.^[11][12][13]

Inflammatory bowel disease (IBD)#edit

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.^[14][15][16]

Biomarker for gut barrier failure#edit

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).^[17] 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.^[17]

• Supervillin

1. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
2. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. ^ a b c d Friederich E, Vancompernolle K, Louvard D, Vandekerckhove J (September 1999). "Villin function in the organization of the actin cytoskeleton. Correlation of in vivo effects to its biochemical activities in vitro". The Journal of Biological Chemistry. 274 (38): 26751–26760. doi:10.1074/jbc.274.38.26751. PMID 10480879.
4. ^ Ghoshdastider U, Popp D, Burtnick LD, Robinson RC (November 2013). "The expanding superfamily of gelsolin homology domain proteins". Cytoskeleton. 70 (11). Hoboken, N.J.: 775–795. doi:10.1002/cm.21149. PMID 24155256. S2CID 205643538.
5. ^ a b c d Bazari WL, Matsudaira P, Wallek M, Smeal T, Jakes R, Ahmed Y (July 1988). "Villin sequence and peptide map identify six homologous domains". Proceedings of the National Academy of Sciences of the United States of America. 85 (14): 4986–4990. Bibcode:1988PNAS...85.4986B. doi:10.1073/pnas.85.14.4986. PMC 281672. PMID 2839826.
6. ^ a b Klahre U, Friederich E, Kost B, Louvard D, Chua NH (January 2000). "Villin-like actin-binding proteins are expressed ubiquitously in Arabidopsis". Plant Physiology. 122 (1): 35–48. Bibcode:2000PlanP.122...35K. doi:10.1104/pp.122.1.35. PMC 58842. PMID 10631247.
7. ^ a b c d Meng J, Vardar D, Wang Y, Guo HC, Head JF, McKnight CJ (September 2005). "High-resolution crystal structures of villin headpiece and mutants with reduced F-actin binding activity". Biochemistry. 44 (36): 11963–11973. doi:10.1021/bi050850x. PMID 16142894.
8. ^ Panebra A, Ma SX, Zhai LW, Wang XT, Rhee SG, Khurana S (September 2001). "Regulation of phospholipase C-gamma(1) by the actin-regulatory protein villin". American Journal of Physiology. Cell Physiology. 281 (3): C1046–58. doi:10.1152/ajpcell.2001.281.3.C1046. PMID 11502583. S2CID 12089989.
9. ^ George SP, Wang Y, Mathew S, Srinivasan K, Khurana S (September 2007). "Dimerization and actin-bundling properties of villin and its role in the assembly of epithelial cell brush borders". The Journal of Biological Chemistry. 282 (36): 26528–26541. doi:10.1074/jbc.M703617200. PMID 17606613.
10. ^ Revenu C, Courtois M, Michelot A, Sykes C, Louvard D, Robine S (2007). "Villin severing activity enhances actin-based motility in vivo". Molecular Biology of the Cell. 18 (3): 827–838. doi:10.1091/mbc.E06-05-0423. PMC 1805090. PMID 17182858.
11. ^ Friederich E, Vancompernolle K, Louvard D, Vandekerckhove J (September 1999). "Villin Function in the Organization of the Actin Cytoskeleton". Journal of Biological Chemistry. 274 (38): 26751–26760. doi:10.1074/jbc.274.38.26751.
12. ^ Wang Y, Srinivasan K, Siddiqui MR, George SP, Tomar A, Khurana S (April 2008). "A novel role for villin in intestinal epithelial cell survival and homeostasis". The Journal of Biological Chemistry. 283 (14): 9454–9464. doi:10.1074/jbc.M707962200. PMID 18198174.
13. ^ Wang Y, George SP, Roy S, Pham E, Esmaeilniakooshkghazi A, Khurana S (October 2016). "Both the anti- and pro-apoptotic functions of villin regulate cell turnover and intestinal homeostasis". Scientific Reports. 6 (1) 35491. Bibcode:2016NatSR...635491W. doi:10.1038/srep35491. PMC 5073230. PMID 27765954.
14. ^ Roy S, Esmaeilniakooshkghazi A, Patnaik S, Wang Y, George SP, Ahrorov A, et al. (April 2018). "Villin-1 and Gelsolin Regulate Changes in Actin Dynamics That Affect Cell Survival Signaling Pathways and Intestinal Inflammation". Gastroenterology. 154 (5): 1405–1420.e2. doi:10.1053/j.gastro.2017.12.016. PMC 7808315. PMID 29274870.
15. ^ Banerjee S, Oneda B, Yap LM, Jewell DP, Matters GL, Fitzpatrick LR, et al. (May 2009). "MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease". Mucosal Immunology. 2 (3): 220–231. doi:10.1038/mi.2009.3. PMC 2670347. PMID 19262505.
16. ^ Dahan S, Rabinowitz KM, Martin AP, Berin MC, Unkeless JC, Mayer L (February 2011). "Notch-1 signaling regulates intestinal epithelial barrier function, through interaction with CD4+ T cells, in mice and humans". Gastroenterology. 140 (2): 550–559. doi:10.1053/j.gastro.2010.10.057. PMC 3031772. PMID 21056041.
17. ^ a b Tornai D, Balogh B, Csillag A, Budai A, Kiss A, Antal-Szalmas P, et al. (April 2026). "Serum Villin-1-A Novel Marker of Gut Barrier Damage in Acutely Decompensated Cirrhosis: A Cohort Study and Validation". Alimentary Pharmacology & Therapeutics. 63 (7) apt.70481. doi:10.1111/apt.70481. hdl:1887/4295442. PMC 12982645. PMID 41340228.

• "The Villin Family". The University of Edinburgh. 2000.
• Zhai L, Zhao P, Panebra A, Guerrerio AL, Khurana S (September 2001). "Tyrosine phosphorylation of villin regulates the organization of the actin cytoskeleton". The Journal of Biological Chemistry. 276 (39): 36163–36167. doi:10.1074/jbc.C100418200. PMID 11500485.
• Kumar N, Tomar A, Parrill AL, Khurana S (October 2004). "Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin". The Journal of Biological Chemistry. 279 (43): 45036–45046. doi:10.1074/jbc.M405424200. PMID 15272027.
• Tomar A, Wang Y, Kumar N, George S, Ceacareanu B, Hassid A, et al. (November 2004). "Regulation of cell motility by tyrosine phosphorylated villin". Molecular Biology of the Cell. 15 (11): 4807–4817. doi:10.1091/mbc.e04-05-0431. PMC 524729. PMID 15342783.
• Rieder G, Tessier AJ, Qiao XT, Madison B, Gumucio DL, Merchant JL (February 2005). "Helicobacter-induced intestinal metaplasia in the stomach correlates with Elk-1 and serum response factor induction of villin". The Journal of Biological Chemistry. 280 (6): 4906–4912. doi:10.1074/jbc.M413399200. PMID 15576363.
• Khurana S, Tomar A, George SP, Wang Y, Siddiqui MR, Guo H, et al. (February 2008). "Autotaxin and lysophosphatidic acid stimulate intestinal cell motility by redistribution of the actin modifying protein villin to the developing lamellipodia". Experimental Cell Research. 314 (3): 530–542. doi:10.1016/j.yexcr.2007.10.028. PMC 2680351. PMID 18054784.
• Khurana S, George SP (June 2008). "Regulation of cell structure and function by actin-binding proteins: villin's perspective". FEBS Letters. 582 (14): 2128–2139. doi:10.1016/j.febslet.2008.02.040. PMC 2680319. PMID 18307996.
• Yamamichi N, Inada K, Furukawa C, Sakurai K, Tando T, Ishizaka A, et al. (June 2009). "Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells". Experimental Cell Research. 315 (10): 1779–1789. doi:10.1016/j.yexcr.2009.01.006. PMID 19371634.
• Nakamura E, Iwakawa M, Furuta R, Ohno T, Satoh T, Nakawatari M, et al. (June 2009). "Villin1, a novel diagnostic marker for cervical adenocarcinoma". Cancer Biology & Therapy. 8 (12): 1146–1153. doi:10.4161/cbt.8.12.8477. PMID 19377296.

• Villin at the U.S. National Library of Medicine Medical Subject Headings (MeSH)