| Structural highlights
Disease
[VILI_HUMAN] Note=Biliary atresia is a chronic and progressive cholestatic liver disease of chilhood characterized by an abnormal villin gene expression and severe malformation of canalicular microvillus structure.
Function
[VILI_HUMAN] Epithelial cell-specific Ca(2+)-regulated actin-modifying protein that modulates the reorganization of microvillar actin filaments. Plays a role in the actin nucleation, actin filament bundle assembly, actin filament capping and severing. Binds phosphatidylinositol 4,5-bisphosphate (PIP2) and lysophosphatidic acid (LPA); binds LPA with higher affinity than PIP2. Binding to LPA increases its phosphorylation by SRC and inhibits all actin-modifying activities. Binding to PIP2 inhibits actin-capping and -severing activities but enhances actin-bundling activity. Regulates the intestinal epithelial cell morphology, cell invasion, cell migration and apoptosis. Protects against apoptosis induced by dextran sodium sulfate (DSS) in the gastrointestinal epithelium. Appears to regulate cell death by maintaining mitochondrial integrity. Enhances hepatocyte growth factor (HGF)-induced epithelial cell motility, chemotaxis and wound repair. Upon S.flexneri cell infection, its actin-severing activity enhances actin-based motility of the bacteria and plays a role during the dissemination.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Villin and gelsolin consist of six homologous domains of the gelsolin/cofilin fold (V1-V6 and G1-G6, respectively). Villin differs from gelsolin in possessing at its C terminus an unrelated seventh domain, the villin headpiece. Here, we present the crystal structure of villin domain V6 in an environment in which intact villin would be inactive, in the absence of bound Ca(2+) or phosphorylation. The structure of V6 more closely resembles that of the activated form of G6, which contains one bound Ca(2+), rather than that of the calcium ion-free form of G6 within intact inactive gelsolin. Strikingly apparent is that the long helix in V6 is straight, as found in the activated form of G6, as opposed to the kinked version in inactive gelsolin. Molecular dynamics calculations suggest that the preferable conformation for this helix in the isolated G6 domain is also straight in the absence of Ca(2+) and other gelsolin domains. However, the G6 helix bends in intact calcium ion-free gelsolin to allow interaction with G2 and G4. We suggest that a similar situation exists in villin. Within the intact protein, a bent V6 helix, when triggered by Ca(2+), straightens and helps push apart adjacent domains to expose actin-binding sites within the protein. The sixth domain in this superfamily of proteins serves as a keystone that locks together a compact ensemble of domains in an inactive state. Perturbing the keystone initiates reorganization of the structure to reveal previously buried actin-binding sites.
Helix straightening as an activation mechanism in the gelsolin superfamily of actin regulatory proteins.,Wang H, Chumnarnsilpa S, Loonchanta A, Li Q, Kuan YM, Robine S, Larsson M, Mihalek I, Burtnick LD, Robinson RC J Biol Chem. 2009 Aug 7;284(32):21265-9. Epub 2009 Jun 1. PMID:19491107[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Northrop J, Weber A, Mooseker MS, Franzini-Armstrong C, Bishop MF, Dubyak GR, Tucker M, Walsh TP. Different calcium dependence of the capping and cutting activities of villin. J Biol Chem. 1986 Jul 15;261(20):9274-81. PMID:3087992
- ↑ Zhai L, Zhao P, Panebra A, Guerrerio AL, Khurana S. Tyrosine phosphorylation of villin regulates the organization of the actin cytoskeleton. J Biol Chem. 2001 Sep 28;276(39):36163-7. Epub 2001 Aug 10. PMID:11500485 doi:10.1074/jbc.C100418200
- ↑ Kumar N, Zhao P, Tomar A, Galea CA, Khurana S. Association of villin with phosphatidylinositol 4,5-bisphosphate regulates the actin cytoskeleton. J Biol Chem. 2004 Jan 23;279(4):3096-110. Epub 2003 Nov 1. PMID:14594952 doi:10.1074/jbc.M308878200
- ↑ Kumar N, Khurana S. Identification of a functional switch for actin severing by cytoskeletal proteins. J Biol Chem. 2004 Jun 11;279(24):24915-8. Epub 2004 Apr 14. PMID:15084600 doi:10.1074/jbc.C400110200
- ↑ Kumar N, Tomar A, Parrill AL, Khurana S. Functional dissection and molecular characterization of calcium-sensitive actin-capping and actin-depolymerizing sites in villin. J Biol Chem. 2004 Oct 22;279(43):45036-46. Epub 2004 Jul 21. PMID:15272027 doi:10.1074/jbc.M405424200
- ↑ Tomar A, Wang Y, Kumar N, George S, Ceacareanu B, Hassid A, Chapman KE, Aryal AM, Waters CM, Khurana S. Regulation of cell motility by tyrosine phosphorylated villin. Mol Biol Cell. 2004 Nov;15(11):4807-17. Epub 2004 Sep 1. PMID:15342783 doi:10.1091/mbc.E04-05-0431
- ↑ Tomar A, George S, Kansal P, Wang Y, Khurana S. Interaction of phospholipase C-gamma1 with villin regulates epithelial cell migration. J Biol Chem. 2006 Oct 20;281(42):31972-86. Epub 2006 Aug 18. PMID:16921170 doi:10.1074/jbc.M604323200
- ↑ Wang Y, Tomar A, George SP, Khurana S. Obligatory role for phospholipase C-gamma(1) in villin-induced epithelial cell migration. Am J Physiol Cell Physiol. 2007 May;292(5):C1775-86. Epub 2007 Jan 17. PMID:17229814 doi:10.1152/ajpcell.00420.2006
- ↑ George SP, Wang Y, Mathew S, Srinivasan K, Khurana S. Dimerization and actin-bundling properties of villin and its role in the assembly of epithelial cell brush borders. J Biol Chem. 2007 Sep 7;282(36):26528-41. Epub 2007 Jul 2. PMID:17606613 doi:10.1074/jbc.M703617200
- ↑ Revenu C, Courtois M, Michelot A, Sykes C, Louvard D, Robine S. Villin severing activity enhances actin-based motility in vivo. Mol Biol Cell. 2007 Mar;18(3):827-38. Epub 2006 Dec 20. PMID:17182858 doi:10.1091/mbc.E06-05-0423
- ↑ Khurana S, Tomar A, George SP, Wang Y, Siddiqui MR, Guo H, Tigyi G, Mathew S. Autotaxin and lysophosphatidic acid stimulate intestinal cell motility by redistribution of the actin modifying protein villin to the developing lamellipodia. Exp Cell Res. 2008 Feb 1;314(3):530-42. Epub 2007 Nov 12. PMID:18054784 doi:10.1016/j.yexcr.2007.10.028
- ↑ Wang Y, Srinivasan K, Siddiqui MR, George SP, Tomar A, Khurana S. A novel role for villin in intestinal epithelial cell survival and homeostasis. J Biol Chem. 2008 Apr 4;283(14):9454-64. doi: 10.1074/jbc.M707962200. Epub 2008, Jan 15. PMID:18198174 doi:10.1074/jbc.M707962200
- ↑ Tomar A, George SP, Mathew S, Khurana S. Differential effects of lysophosphatidic acid and phosphatidylinositol 4,5-bisphosphate on actin dynamics by direct association with the actin-binding protein villin. J Biol Chem. 2009 Dec 18;284(51):35278-82. doi: 10.1074/jbc.C109.060830. Epub . PMID:19808673 doi:10.1074/jbc.C109.060830
- ↑ Wang H, Chumnarnsilpa S, Loonchanta A, Li Q, Kuan YM, Robine S, Larsson M, Mihalek I, Burtnick LD, Robinson RC. Helix straightening as an activation mechanism in the gelsolin superfamily of actin regulatory proteins. J Biol Chem. 2009 Aug 7;284(32):21265-9. Epub 2009 Jun 1. PMID:19491107 doi:10.1074/jbc.M109.019760
|
