Vinculin

Source: Wikipedia, the free encyclopedia.
See also: Vinculin family
VCL
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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

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

Vinculin is a 117-kDa cytoskeletal protein with 1066

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 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

Cell spreading and movement occur through the process of binding of cell surface

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, 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.

Activation

Vinculin is present in equilibrium between an active and inactive state.

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.[10]

Binding site

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

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.[11]

Splice variants

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.[12] 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.[13]

The length of the insert in metavinculin is 68 AA in mammals and 79 in frog.

cardiomyocytes, and costameres in skeletal muscles.[15]
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

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.[22]

References

  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. S2CID 33153559
    .
  6. S2CID 43087259
    .
  7. ^
    PMID 11785963
    .
  8. PMID 9486805
    .
  9. ^
    PMID 9056408
    .
  10. ^
    PMID 15242595
    .
  11. PMID 16460027
    .
  12. PMID 6809764
    .
  13. PMID 15159399
    .
  14. S2CID 39567003
    .
  15. PMID 3138246
    .
  16. PMID 9405455
    .
  17. PMID 9535896
    .
  18. PMID 10330411
    .
  19. PMID 9054445
    .
  20. PMID 8922390
    .
  21. PMID 10085297
    .
  22. S2CID 22408999
    .

Further reading

External links
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