Testinalso known as
TESSis a
proteinthat in humans is encoded by the
TESgenelocated on
chromosome7.TES is a 47
kDaprotein composed of 421
amino acidsfound atfocal adhesionsand is thought to have a role in regulation ofcell motility.In addition to this, TES functions as atumoursuppressor.The
TESgene is located within a fragile region ofchromosome 7, and the
promoterelements of the
TESgene have been shown to be susceptible tomethylation- this prevents the
expressionof the TES protein. TES came to greater prominence towards the end of 2007 as a potential mechanism for itstumour suppressor functionwas published.
TESTES as a tumour suppressor[edit]
语音In December 2007, Boeda, Briggs
et al.showed that the third LIM domain of TES displaces Mena from its usual subcellular positions (focal adhesionsor the cell leading edge). The ENA/VASP protein family (of which Mena is a member) are anchored to specific proteins within the cell by a
peptidemotif consisting of a
phenylalanineresidue, followed by four
prolineresidues - known as a FPPPP motif. It is theEVH1 domainsof VASP/EVL proteins that directly contact the FPPPP motif. The precise architecture of TES:MENA binding was revealed byX-ray crystallography, and showed that the 3rd LIM domain of TES covered up the FPPPP binding site within Menas EVH1 domain.Isothermal titration calorimetryshowed that TES has a greater affinity for Mena than its canonical FPPPP ligand, as presented in the focal adhesion protein zyxin. Using microscopy it was shown that either over-expression of
GFP-tagged TES, or just the tagged third LIM domain displaced Mena from focal adhesions and reduced mean cell velocity.
These finding were significant given that Mena is often over-expressed in
cancercells, and is thought to be partly responsible for cancer cell motility, and therefore a factor in cancer
metastasis. TES is conversely often not produced in cancer cells. It is possible that a drug designed to mimic TES's interaction with Mena could be used to prevent metastasis and thus development of secondary tumours in cancer patients. The work was widely reported in the British press (the work was carried out byCancer Research UK),and also in the international press.
TESConformational Change[edit]
语音Based on the observations that:
Mammalian cell derived TES binding Zyxin
E. coliproducedrecombinantTES (rTES) does not bind Zyxin
An rTES construct composed of residues 201-421 (i.e., the linker and all 3 LIM domains) does bind Zyxin
The above rTES construct binds an N-terminal rTES construct, consisting of the cysteine rich and PET domains -IE, the two halves of TES interact with each other.
Garvalovet al.propose that TES exists in two conformational states: A 'closed' state where the N & C halves of TES interact, obscuring the Zyxin binding site in LIM1, and an 'open' state where the Zyxin binding site is accessible and the two halves no-longer interact in the same fashion, if at all. The regulatory mechanism switching between the two states is not presently fully understood.
In
RNAiexperiments, cells that had impaired TES expression showed an inability to correctly organise theirfocal adhesionsand
actinstress fibres.
In gene knockout experiments,transgenicmice lacking both copies of the TES gene displayed an increased susceptibility totumourformation when challenged with a carcinogen. Mice retaining the TES gene were less susceptible: thus, TES is a tumour suppressor gene.
Testin, TESS, 或Tes，一种被第七染色体上的Tes基因编辑形成的蛋白质。Tes是一个在焦点粘连处被发现的由421个氨基酸组成的47 kDa的蛋白质；对管理细胞活性有一定的影响。同时也对肿瘤的发展有一定的抑制作用。Tes基因位于第七染色体薄弱位置，2007年确认它有肿瘤抑制功能使之名声大旺。
