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Vinculin

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(Redirected from MVCL)
See also: Vinculin family
VCL
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesVCL, CMD1W, CMH15, HEL114, MV, Mvinculin
External IDsOMIM: 193065; MGI: 98927; HomoloGene: 7594; GeneCards: VCL; OMA:VCL - orthologs
Orthologs
SpeciesHumanMouse
Entrez

7414

22330

Ensembl

ENSG00000035403

ENSMUSG00000021823

UniProt

P18206

Q64727

RefSeq (mRNA)

NM_003373
NM_014000

NM_009502

RefSeq (protein)

NP_003364
NP_054706

NP_033528

Location (UCSC)Chr 10: 74 – 74.12 MbChr 14: 20.98 – 21.08 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Vinculin is a globular protein approximately 115 x 85 x 65 angstroms in linear dimension.

In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton. Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane.

Discovered independently by Benny Geiger[5] and Keith Burridge,[6] its sequence is 20%–30% similar to α-catenin, which serves a similar function.

Binding alternately to talin or α-actinin, vinculin's shape and, as a consequence, its binding properties are changed. The vinculin gene occurs as a single copy and what appears to be no close relative to take over functions in its absence. Its splice variant metavinculin (see below) also needs vinculin to heterodimerize and work in a dependent fashion.

Structure

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Vinculin is a 117-kDa cytoskeletal protein with 1066 amino acids. The protein contains an acidic N-terminal domain and a basic C-terminal domain separated by a proline-rich middle segment. Vinculin consists of a globular head domain that contains binding sites for talin and α-actinin as well as a tyrosine phosphorylation site, while the tail region contains binding sites for F-actin, paxillin, and lipids.[7]

Essentially, there is an 835 amino acid N-terminal head, which is split into four domains. This is linked to the C-terminal tail with a linker region.

The recent discovery of the 3D structure[citation needed] sheds light on how this protein tailors its shape to perform a variety of functions. For example, vinculin is able to control the cell's motility by simply altering its shape from active to inactive. When in its ‘inactive’ state, vinculin's conformation is characterized by the interaction between its head and tail domains. And, when transforming to the ‘active’ form, such as when talin triggers binding, the intramolecular interaction between the tail and head is severed. In other words, when talin's binding sites (VBS) of α-helices bind to a helical bundle structure in vinculin's head domain, the ‘helical bundle conversion’ is initiated, which leads to the reorganization of the α-helices (α1- α-4), resulting in an entirely new five-helical bundle structure. This function also extends to cancer cells, and regulating their movement and proliferation of cancer to other parts of the body.

Mechanism and function

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Cell spreading and movement occur through the process of binding of cell surface integrin receptors to extracellular matrix adhesion molecules. Vinculin is associated with focal adhesion and adherens junctions, resulting in significant protein dynamics[citation needed]. These are complexes that nucleate actin filaments and crosslinkers between the external medium, plasma membrane, and actin cytoskeleton.[8] The complex at the focal adhesions consists of several proteins such as vinculin, α-actinin, paxillin, and talin, at the intracellular face of the plasma membrane.

In more specific terms, the amino-terminus of vinculin binds to talin, which, in turn, binds to β-integrins, and the carboxy-terminus binds to actin, phospholipids, and paxillin-forming homodimers. The binding of vinculin to talin and actin is regulated by polyphosphoinositides and inhibited by acidic phospholipids. The complex then serves to anchor actin filaments to the membrane and thus, helps to reinforce force on talin within the focal adhesions.[9]

The loss of vinculin impacts a variety of cell functions; it disrupts the formation of the complex, and prevents cell adhesion and spreading. The absence of the protein demonstrates a decrease in spreading of cells, accompanied by reduced stress fiber formation, formation of fewer focal adhesions, and inhibition of lamellipodia extension.[7] It was discovered that cells that are deficient in vinculin have growth cones that advance more slowly, as well as filopodia and lamellipodia that were less stable than the wild-type. Based on research[citation needed], it has been postulated that the lack of vinculin may decrease cell adhesion by inhibiting focal adhesion assembly and preventing actin polymerization. On the other hand, overexpression of vinculin may restore adhesion and spreading by promoting recruitment of cytoskeletal proteins to the focal adhesion complex at the site of integrin binding.[9] Vinculin's ability to interact with integrins to the cytoskeleton at the focal adhesion appears to be critical for control of cytoskeletal mechanics, cell spreading, and lamellipodia formation. Thus, vinculin appears to play a key role in shape control based on its ability to modulate focal adhesion structure and function.[10]

Activation

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Vinculin is present in equilibrium between an active and inactive state.[11] The active state is triggered upon binding to its designated partner. These changes occur when vinculin interacts with focal adhesion points to which it is binding to. When vinculin resides in its inactive form, the protein is kept designated to the cytoplasm unlike the focal adhesion points bound from the active state. The molecule talin is thought to be the major initiator of vinculin activation due to its presence in focal complexes. The combinatorial model of vinculin states that either α-actinin or talin can activate vinculin either alone or with the assistance of PIP2 or actin. This activation takes place by separation of the head-tail connection within inactive vinculin.[11]

Binding site

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VBS
human vinculin head (1-258) in complex with talin's vinculin binding site 3 (residues 1944-1969)
Identifiers
SymbolVBS
PfamPF08913
InterProIPR015009
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Vinculin binding sites are predominantly found in talin and talin-like molecules, enabling binding of vinculin to talin, stabilising integrin-mediated cell-matrix junctions. Talin, in turn, links integrins to the actin cytoskeleton. The consensus sequence for Vinculin binding sites is LxxAAxxVAxxVxxLIxxA, with a secondary structure prediction of four amphipathic helices. The hydrophobic residues that define the VBS are themselves 'masked' and are buried in the core of a series of helical bundles that make up the talin rod.[12]

Splice variants

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Smooth muscles and skeletal muscles (and probably to a lower extent in cardiac muscle) in their well-differentiated (contractile) state co-express (along with vinculin) a splice variant carrying an extra exon in the 3' coding region, thus encoding a longer isoform meta-vinculin (meta VCL) of ~150KD molecular weight — a protein whose existence has been known since the 1980s.[13] Translation of the extra exon causes a 68- to 79-amino acid acid-rich insert between helices I and II within the C-terminal tail domain. Mutations within the insert region correlate with hereditary idiopathic dilated cardiomyopathy.[14]

The length of the insert in metavinculin is 68 AA in mammals and 79 in frog.[15] Compared metavinculin sequences from pig, man, chicken, and frog, and found the insert to be bipartite: the first part variable and the second highly conserved. Both vinculin isoforms co-localize in muscular adhesive structures, such as dense plaques in smooth muscles, intercalated discs in cardiomyocytes, and costameres in skeletal muscles.[16] Metavinculin tail domain has a lower affinity for the head as compared with the vinculin tail. In case of metavinculin, unfurling of the C-terminal hydrophobic hairpin loop of tail domain is impaired by the negative charges of the 68-amino acid insert, thus requiring phospholipid-activated regular isoform of vinculin to fully activate the metavinculin molecule.

Interactions

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Vinculin has been shown to interact with:

In cases of Small Intestinal Bacterial Overgrowth presented as IBS symptoms, anti-CdtB antibodies have been identified to affect vinculin function, which is required in gut motility.[23]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000035403 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021823 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Geiger B (September 1979). "A 130K protein from chicken gizzard: its localization at the termini of microfilament bundles in cultured chicken cells". Cell. 18 (1): 193–205. doi:10.1016/0092-8674(79)90368-4. PMID 574428. S2CID 33153559.
  6. ^ Burridge K, Feramisco JR (March 1980). "Microinjection and localization of a 130K protein in living fibroblasts: a relationship to actin and fibronectin". Cell. 19 (3): 587–95. doi:10.1016/s0092-8674(80)80035-3. PMID 6988083. S2CID 43087259.
  7. ^ a b Goldmann WH, Ingber DE (January 2002). "Intact vinculin protein is required for control of cell shape, cell mechanics, and rac-dependent lamellipodia formation". Biochemical and Biophysical Research Communications. 290 (2): 749–55. doi:10.1006/bbrc.2001.6243. PMID 11785963.
  8. ^ Xu W, Baribault H, Adamson ED (January 1998). "Vinculin knockout results in heart and brain defects during embryonic development". Development. 125 (2): 327–37. doi:10.1242/dev.125.2.327. PMID 9486805.
  9. ^ a b Ezzell RM, Goldmann WH, Wang N, Parashurama N, Parasharama N, Ingber DE (February 1997). "Vinculin promotes cell spreading by mechanically coupling integrins to the cytoskeleton". Experimental Cell Research. 231 (1): 14–26. doi:10.1006/excr.1996.3451. PMID 9056408.
  10. ^ Callaway DJ, Nicholl ID, Shi B, Reyes G, Farago B, Bu Z (2024). "Nanoscale dynamics of the cadherin-catenin complex bound to vinculin revealed by neutron spin echo spectroscopy". Proceedings of the National Academy of Sciences of the United States of America. 129 (39). doi:10.1073/pnas.2408459121. PMC 11441495. PMID 39298480.
  11. ^ a b Borgon RA, Vonrhein C, Bricogne G, Bois PR, Izard T (July 2004). "Crystal structure of human vinculin". Structure. 12 (7): 1189–97. doi:10.1016/j.str.2004.05.009. PMID 15242595.
  12. ^ Gingras AR, Vogel KP, Steinhoff HJ, Ziegler WH, Patel B, Emsley J, Critchley DR, Roberts GC, Barsukov IL (February 2006). "Structural and dynamic characterization of a vinculin binding site in the talin rod". Biochemistry. 45 (6): 1805–17. doi:10.1021/bi052136l. PMID 16460027.
  13. ^ Feramisco JR, Smart JE, Burridge K, Helfman DM, Thomas GP (September 1982). "Co-existence of vinculin and a vinculin-like protein of higher molecular weight in smooth muscle". The Journal of Biological Chemistry. 257 (18): 11024–31. doi:10.1016/S0021-9258(18)33927-9. PMID 6809764.
  14. ^ Witt S, Zieseniss A, Fock U, Jockusch BM, Illenberger S (July 2004). "Comparative biochemical analysis suggests that vinculin and metavinculin cooperate in muscular adhesion sites". The Journal of Biological Chemistry. 279 (30): 31533–43. doi:10.1074/jbc.M314245200. PMID 15159399.
  15. ^ Strasser P, Gimona M, Herzog M, Geiger B, Small JV (February 1993). "Variable and constant regions in the C-terminus of vinculin and metavinculin. Cloning and expression of fragments in E. coli". FEBS Letters. 317 (3): 189–94. doi:10.1016/0014-5793(93)81274-4. PMID 8425604. S2CID 39567003.
  16. ^ Belkin AM, Ornatsky OI, Glukhova MA, Koteliansky VE (August 1988). "Immunolocalization of meta-vinculin in human smooth and cardiac muscles". The Journal of Cell Biology. 107 (2): 545–53. doi:10.1083/jcb.107.2.545. PMC 2115213. PMID 3138246.
  17. ^ Hazan RB, Kang L, Roe S, Borgen PI, Rimm DL (December 1997). "Vinculin is associated with the E-cadherin adhesion complex". The Journal of Biological Chemistry. 272 (51): 32448–53. doi:10.1074/jbc.272.51.32448. PMID 9405455.
  18. ^ Hazan RB, Norton L (April 1998). "The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton". The Journal of Biological Chemistry. 273 (15): 9078–84. doi:10.1074/jbc.273.15.9078. PMID 9535896.
  19. ^ Turner CE, Brown MC, Perrotta JA, Riedy MC, Nikolopoulos SN, McDonald AR, Bagrodia S, Thomas S, Leventhal PS (May 1999). "Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling". The Journal of Cell Biology. 145 (4): 851–63. doi:10.1083/jcb.145.4.851. PMC 2133183. PMID 10330411.
  20. ^ Mazaki Y, Hashimoto S, Sabe H (March 1997). "Monocyte cells and cancer cells express novel paxillin isoforms with different binding properties to focal adhesion proteins". The Journal of Biological Chemistry. 272 (11): 7437–44. doi:10.1074/jbc.272.11.7437. PMID 9054445.
  21. ^ Brown MC, Perrotta JA, Turner CE (November 1996). "Identification of LIM3 as the principal determinant of paxillin focal adhesion localization and characterization of a novel motif on paxillin directing vinculin and focal adhesion kinase binding". The Journal of Cell Biology. 135 (4): 1109–23. doi:10.1083/jcb.135.4.1109. PMC 2133378. PMID 8922390.
  22. ^ Mandai K, Nakanishi H, Satoh A, Takahashi K, Satoh K, Nishioka H, Mizoguchi A, Takai Y (March 1999). "Ponsin/SH3P12: an l-afadin- and vinculin-binding protein localized at cell-cell and cell-matrix adherens junctions". The Journal of Cell Biology. 144 (5): 1001–17. doi:10.1083/jcb.144.5.1001. PMC 2148189. PMID 10085297.
  23. ^ Pimentel M, Morales W, Pokkunuri V, Brikos C, Kim SM, Kim SE, Triantafyllou K, Weitsman S, Marsh Z, Marsh E, Chua KS, Srinivasan S, Barlow GM, Chang C (May 2015). "Autoimmunity Links Vinculin to the Pathophysiology of Chronic Functional Bowel Changes Following Campylobacter jejuni Infection in a Rat Model". Digestive Diseases and Sciences. 60 (5): 1195–205. doi:10.1007/s10620-014-3435-5. PMID 25424202. S2CID 22408999.

Further reading

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  • Overview of all the structural information available in the PDB for UniProt: P18206 (Human Vinculin) at the PDBe-KB.
  • Overview of all the structural information available in the PDB for UniProt: Q64727 (Mouse Vinculin) at the PDBe-KB.
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