{{Short description|Actin-binding protein}} {{Infobox_gene}} {{protein |Name=Villin-1 |caption= |image= |width= |HGNCid=12690 |Symbol=VIL1 |AltSymbols=VIL |EntrezGene=7429 |OMIM=193040 |RefSeq=NM_007127 |UniProt=P09327 |PDB= |ECnumber= |Chromosome=2 |Arm=q |Band=35 |LocusSupplementaryData=-q36 }} [[File:Villin-1qqv.png|thumb|right|300px|The helix bundle in the headpiece domain of chicken villin.]] '''Villin-1''' is a 92.5 kDa tissue-specific actin-binding protein associated with the actin core bundle of the brush border.<ref name="Friederich">{{cite journal | vauthors = Friederich E, Vancompernolle K, Louvard D, Vandekerckhove J | title = Villin function in the organization of the actin cytoskeleton. Correlation of in vivo effects to its biochemical activities in vitro | journal = The Journal of Biological Chemistry | volume = 274 | issue = 38 | pages = 26751–60 | date = September 1999 | pmid = 10480879 | doi = 10.1074/jbc.274.38.26751 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Ghoshdastider U, Popp D, Burtnick LD, Robinson RC | title = The expanding superfamily of gelsolin homology domain proteins | journal = Cytoskeleton | volume = 70 | issue = 11 | pages = 775–95 | date = November 2013 | pmid = 24155256 | doi = 10.1002/cm.21149 | s2cid = 205643538 }}</ref> The headpiece domain is a commonly studied protein in molecular dynamics due to its small size and fast folding kinetics and short primary sequence.<ref name="Bazari">{{cite journal | vauthors = Bazari WL, Matsudaira P, Wallek M, Smeal T, Jakes R, Ahmed Y | title = Villin sequence and peptide map identify six homologous domains | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 14 | pages = 4986–90 | date = July 1988 | pmid = 2839826 | pmc = 281672 | doi = 10.1073/pnas.85.14.4986 | bibcode = 1988PNAS...85.4986B | doi-access = free }}</ref><ref name="Klahre">{{cite journal | vauthors = Klahre U, Friederich E, Kost B, Louvard D, Chua NH | title = Villin-like actin-binding proteins are expressed ubiquitously in Arabidopsis | journal = Plant Physiology | volume = 122 | issue = 1 | pages = 35–48 | date = January 2000 | pmid = 10631247 | pmc = 58842 | doi = 10.1104/pp.122.1.35 | bibcode = 2000PlanP.122...35K }}</ref>
== Structure == Villin-1 is made up of seven domains, six homologous domains make up the N-terminal core and the remaining domain makes up the C-terminal cap.<ref name="Bazari" /> Villin contains three phosphatidylinositol 4,5-biphosphate (PIP<sub>2</sub>) binding sites, one of which is located at the head piece and the other two in the core.<ref name="Meng">{{cite journal | vauthors = Meng J, Vardar D, Wang Y, Guo HC, Head JF, McKnight CJ | title = High-resolution crystal structures of villin headpiece and mutants with reduced F-actin binding activity | journal = Biochemistry | volume = 44 | issue = 36 | pages = 11963–73 | date = September 2005 | pmid = 16142894 | doi = 10.1021/bi050850x }}</ref> The core domain is approximately 150 amino acid residues grouped in six repeats. On this core is an 87 residue, hydrophobic, C-terminal headpiece<ref name="Friederich" /> The headpiece (HP67) is made up of a compact, 70 amino acid folded protein at the C-terminus. This headpiece contains an F-actin binding domain. Residues K38, E39, K65, 70-73:KKEK, G74, L75 and F76 surround a hydrophobic core and are believed to be involved in the binding of F-actin to villin-1. Residues E39 and K70 form a salt bridge buried within the headpiece which serves to connect N and C terminals. This salt bridge may also orient and fix the C-terminal residues involved in F-actin binding as in the absence of this salt bridge no binding occurs. A hydrophobic “cap” is formed by residue W64 side chains, which is completely conserved throughout the villin family. Below this cap is a crown of alternative positive and negative charged localities.<ref name="Meng" /> Villin can undergo post-translational modifications like tyrosine phosphorylation.<ref name="Zhai">{{cite journal | vauthors = Panebra A, Ma SX, Zhai LW, Wang XT, Rhee SG, Khurana S | title = Regulation of phospholipase C-gamma(1) by the actin-regulatory protein villin | journal = American Journal of Physiology. Cell Physiology | volume = 281 | issue = 3 | pages = C1046-58 | date = September 2001 | pmid = 11502583 | doi = 10.1152/ajpcell.2001.281.3.C1046 | s2cid = 12089989 }}<!--maybe PMID 11500485 is better?--></ref> Villin-1 has the ability to dimerize and the dimerization site is located at the amino end of the protein.<ref name="George">{{cite journal | vauthors = George SP, Wang Y, Mathew S, Srinivasan K, Khurana S | title = Dimerization and actin-bundling properties of villin and its role in the assembly of epithelial cell brush borders | journal = The Journal of Biological Chemistry | volume = 282 | issue = 36 | pages = 26528–41 | date = September 2007 | pmid = 17606613 | doi = 10.1074/jbc.M703617200 | doi-access = free }}</ref>
== 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.<ref name="Klahre" /> Villin is found localized in the microvilli of the brush border of the epithelium lining of the gut and renal tubules in vertebrates.<ref name="Meng" />
== Function == Villin-1 is believed to function in the bundling, nucleation, capping and severing of actin filaments.<ref name="Friederich" /> 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.<ref name="Meng" /> The six-repeat villin core is responsible for Ca<sup>2+</sup> actin severing while the headpiece is responsible for actin crosslinking and bundling (Ca independent). Villin is postulated to be the controlling protein for Ca<sup>2+</sup> induced actin severing in the brush border. Ca<sup>2+</sup> inhibits proteolytic cleavage of the domains of the 6 N-terminal core which inhibits actin severing.<ref name="Bazari" /> In normal mice raising Ca<sup>2+</sup> levels induces the severing of actin by villin, whereas in villin knockout mice this activity does not occur in response to heightened Ca<sup>2+</sup> levels.<ref name="Curie">{{cite journal | vauthors = Revenu C, Courtois M, Michelot A, Sykes C, Louvard D, Robine S | title = Villin severing activity enhances actin-based motility in vivo | journal = Molecular Biology of the Cell | volume = 18 | issue = 3 | pages = 827–38 | year = 2007 | pmid = 17182858 | pmc = 1805090 | doi = 10.1091/mbc.E06-05-0423 }}</ref> In the presence of low concentrations of Ca<sup>2+</sup> the villin headpiece functions to bundle actin filaments whereas in the presence of high Ca<sup>2+</sup> concentrations the N-terminal caps and severs these filaments.<ref name="Friederich" /> The association of PIP<sub>2</sub> with villin inhibits the actin capping and severing action and increases actin binding at the headpiece region, possibly through structural changes in the protein. PIP<sub>2</sub> 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.<ref name="Bazari" />
== Villin subdomain == The C-terminal subdomain of Villin Headpiece VHP67, denoted VHP35, is stabilised in part, by a buried cluster of three phenylalanine residues. Its small size and high helical content are expected to promote rapid folding, and this has been confirmed experimentally. Villin-4 C-terminal construct VHP76 in Arabidopsis thaliana has been shown to exhibit higher affinity for F-actin in increasing concentrations of Ca<sup>2+</sup>, which further confirms the function of villin.
=== Structure === It has a simple topology consisting of three α-helices that form a well-packed hydrophobic core.
== 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.<ref>{{Cite journal |last1=Friederich |first1=Evelyne |last2=Vancompernolle |first2=Katia |last3=Louvard |first3=Daniel |last4=Vandekerckhove |first4=Joël |date=September 1999 |title=Villin Function in the Organization of the Actin Cytoskeleton |journal=Journal of Biological Chemistry |language=en |volume=274 |issue=38 |pages=26751–26760 |doi=10.1074/jbc.274.38.26751 |doi-access=free }}</ref><ref>{{Cite journal |last1=Wang |first1=Yaohong |last2=Srinivasan |first2=Kamalakkannan |last3=Siddiqui |first3=Mohammad Rizwan |last4=George |first4=Sudeep P. |last5=Tomar |first5=Alok |last6=Khurana |first6=Seema |date=April 2008 |title=A Novel Role for Villin in Intestinal Epithelial Cell Survival and Homeostasis |journal=Journal of Biological Chemistry |language=en |volume=283 |issue=14 |pages=9454–9464 |doi=10.1074/jbc.M707962200 |doi-access=free }}</ref><ref>{{Cite journal |last1=Wang |first1=Yaohong |last2=George |first2=Sudeep P. |last3=Roy |first3=Swati |last4=Pham |first4=Eric |last5=Esmaeilniakooshkghazi |first5=Amin |last6=Khurana |first6=Seema |date=2016-10-21 |title=Both the anti- and pro-apoptotic functions of villin regulate cell turnover and intestinal homeostasis |journal=Scientific Reports |language=en |volume=6 |issue=1 |article-number=35491 |doi=10.1038/srep35491 |issn=2045-2322 |pmc=5073230 |pmid=27765954 |bibcode=2016NatSR...635491W }}</ref>
=== 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.<ref>{{Cite journal |last1=Roy |first1=Swati |last2=Esmaeilniakooshkghazi |first2=Amin |last3=Patnaik |first3=Srinivas |last4=Wang |first4=Yaohong |last5=George |first5=Sudeep P. |last6=Ahrorov |first6=Afzal |last7=Hou |first7=Jason K. |last8=Herron |first8=Alan J. |last9=Sesaki |first9=Hiromi |last10=Khurana |first10=Seema |date=April 2018 |title=Villin-1 and Gelsolin Regulate Changes in Actin Dynamics That Affect Cell Survival Signaling Pathways and Intestinal Inflammation |journal=Gastroenterology |language=en |volume=154 |issue=5 |pages=1405–1420.e2 |doi=10.1053/j.gastro.2017.12.016 |pmc=7808315 |pmid=29274870}}</ref><ref>{{Cite journal |last1=Banerjee |first1=S |last2=Oneda |first2=B |last3=Yap |first3=L M |last4=Jewell |first4=D P |last5=Matters |first5=G L |last6=Fitzpatrick |first6=L R |last7=Seibold |first7=F |last8=Sterchi |first8=E E |last9=Ahmad |first9=T |last10=Lottaz |first10=D |last11=Bond |first11=J S |date=May 2009 |title=MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease |journal=Mucosal Immunology |language=en |volume=2 |issue=3 |pages=220–231 |doi=10.1038/mi.2009.3 |pmc=2670347 |pmid=19262505}}</ref><ref>{{Cite journal |last1=Dahan |first1=Stephanie |last2=Rabinowitz |first2=Keren M. |last3=Martin |first3=Andrea P. |last4=Berin |first4=M. Cecilia |last5=Unkeless |first5=Jay C. |last6=Mayer |first6=Lloyd |date=February 2011 |title=Notch-1 Signaling Regulates Intestinal Epithelial Barrier Function, Through Interaction With CD4+ T Cells, in Mice and Humans |journal=Gastroenterology |language=en |volume=140 |issue=2 |pages=550–559 |doi=10.1053/j.gastro.2010.10.057 |pmc=3031772 |pmid=21056041}}</ref>
=== 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).<ref name=":0">{{Cite journal |last1=Tornai |first1=David |last2=Balogh |first2=Boglarka |last3=Csillag |first3=Aniko |last4=Budai |first4=Andras |last5=Kiss |first5=Andras |last6=Antal-Szalmas |first6=Peter |last7=Mehes |first7=Gabor |last8=Barath |first8=Lukacs |last9=Tornai |first9=Tamas |last10=Tornai |first10=Istvan |last11=Vitalis |first11=Zsuzsanna |last12=Sipeki |first12=Nora |last13=Dinya |first13=Tamas |last14=Enyedi |first14=Attila |last15=Rosenberger |first15=Florian A. |date=2025-12-03 |title=Serum Villin-1—A Novel Marker of Gut Barrier Damage in Acutely Decompensated Cirrhosis: A Cohort Study and Validation |url=https://onlinelibrary.wiley.com/doi/10.1111/apt.70481 |journal=Alimentary Pharmacology & Therapeutics |article-number=apt.70481 |language=en |doi=10.1111/apt.70481 |pmid=41340228 |issn=0269-2813|doi-access=free |hdl=1887/4295442 |hdl-access=free }}</ref> 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.<ref name=":0" />
== See also == * Supervillin
== References == {{Reflist|32em}}
== Further reading == {{refbegin | 30em}} * {{cite web | title = The Villin Family | publisher = The University of Edinburgh | year = 2000 | url = http://www.bms.ed.ac.uk/research/others/smaciver/Cyto-Topics/villin_family.htm }} *{{cite journal |vauthors=Zhai L, Zhao P, Panebra A, Guerrerio AL, Khurana S |title=Tyrosine phosphorylation of villin regulates the organization of the actin cytoskeleton |journal=J. Biol. Chem. |volume=276 |issue=39 |pages=36163–7 |date=September 2001 |pmid=11500485 |doi=10.1074/jbc.C100418200 |doi-access=free }} *{{cite journal |vauthors=Kumar N, Tomar A, Parrill AL, Khurana S |title=Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin |journal=J. Biol. Chem. |volume=279 |issue=43 |pages=45036–46 |date=October 2004 |pmid=15272027 |doi=10.1074/jbc.M405424200 |doi-access=free }} *{{cite journal |vauthors=Tomar A, Wang Y, Kumar N, George S, Ceacareanu B, Hassid A, Chapman KE, Aryal AM, Waters CM, Khurana S |title=Regulation of cell motility by tyrosine phosphorylated villin |journal=Mol. Biol. Cell |volume=15 |issue=11 |pages=4807–17 |date=November 2004 |pmid=15342783 |pmc=524729 |doi=10.1091/mbc.e04-05-0431 }} *{{cite journal |vauthors=Rieder G, Tessier AJ, Qiao XT, Madison B, Gumucio DL, Merchant JL |title=Helicobacter-induced intestinal metaplasia in the stomach correlates with Elk-1 and serum response factor induction of villin |journal=J. Biol. Chem. |volume=280 |issue=6 |pages=4906–12 |date=February 2005 |pmid=15576363 |doi=10.1074/jbc.M413399200 |doi-access=free }} *{{cite journal |vauthors=Revenu C, Courtois M, Michelot A, Sykes C, Louvard D, Robine S |title=Villin severing activity enhances actin-based motility in vivo |journal=Mol. Biol. Cell |volume=18 |issue=3 |pages=827–38 |date=March 2007 |pmid=17182858 |pmc=1805090 |doi=10.1091/mbc.e06-05-0423 }} *{{cite journal |vauthors=Khurana S, Tomar A, George SP, Wang Y, Siddiqui MR, Guo H, Tigyi G, Mathew S |title=Autotaxin and lysophosphatidic acid stimulate intestinal cell motility by redistribution of the actin modifying protein villin to the developing lamellipodia |journal=Exp. Cell Res. |volume=314 |issue=3 |pages=530–42 |date=February 2008 |pmid=18054784 |pmc=2680351 |doi=10.1016/j.yexcr.2007.10.028 }} *{{cite journal |vauthors=Khurana S, George SP |title=Regulation of cell structure and function by actin-binding proteins: villin's perspective |journal=FEBS Lett. |volume=582 |issue=14 |pages=2128–39 |date=June 2008 |pmid=18307996 |pmc=2680319 |doi=10.1016/j.febslet.2008.02.040 }} *{{cite journal |vauthors=Yamamichi N, Inada K, Furukawa C, Sakurai K, Tando T, Ishizaka A, Haraguchi T, Mizutani T, Fujishiro M, Shimomura R, Oka M, Ichinose M, Tsutsumi Y, Omata M, Iba H |title=Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells |journal=Exp. Cell Res. |volume=315 |issue=10 |pages=1779–89 |date=June 2009 |pmid=19371634 |doi=10.1016/j.yexcr.2009.01.006 }} *{{cite journal |vauthors=Nakamura E, Iwakawa M, Furuta R, Ohno T, Satoh T, Nakawatari M, Ishikawa K, Imadome K, Michikawa Y, Tamaki T, Kato S, Kitagawa T, Imai T |title=Villin1, a novel diagnostic marker for cervical adenocarcinoma |journal=Cancer Biol. Ther. |volume=8 |issue=12 |pages=1146–53 |date=June 2009 |pmid=19377296 |doi= 10.4161/cbt.8.12.8477|doi-access=free }} {{Refend}}
== External links == * {{MeshName|Villin}}
Category:Proteins