Biology:TLN2
Generic protein structure example |
Talin 2 is a protein in humans that is encoded by the TLN2 gene. It belongs to the talin protein family. This gene encodes a protein related to talin 1, a cytoskeletal protein that plays a significant role in the assembly of actin filaments. Talin-2 is expressed at high levels in cardiac muscle and functions to provide linkages between the extracellular matrix and actin cytoskeleton at costamere structures to transduce force laterally.[1]
Structure
Human talin-2 is 271.4 kDa and 2542 amino acids in length.[2] The size of talin-2 protein is similar to talin-1, and is relatively similar (74% identity, 86% similarity); the size of the talin-2 gene (200 kb) is however much larger than that of talin-1 (30 kb), due to differences in intron sizes.[3] Talin-2 mRNA is expressed in multiple tissues, including cardiac muscle, mouse embryonic stem cells, brain, lung, skeletal muscle, kidney and testis; however expression is highest in cardiac muscle.[3][4][5][6] A detailed analysis of the TLN2 gene revealed that the alternative splicing of TLN2 is complex and encodes multiple mRNA transcripts and protein isoforms. Studies revealed a promoter associated with a CpG island that accounts for most of the TLN2 expression in adult tissues. This promoter is separated from the first coding exon by approximately > 200 kb of alternatively spliced noncoding exons. The testis and kidney talin-2 isoforms lack the N-terminal 50% of the protein, and evidence suggests that this is the isoform expressed in elongating spermatids.[7] Talin is also post-translationally modified via calpain 2-mediated cleavage, which may target it for ubiquitin-proteasome-mediated degradation and turnover of associated cell adhesion structures.[8]
Function
The expression of talin-2 in striated muscle is developmentally regulated. Undifferentiated myoblasts primarily express talin-1, and both mRNA and protein expression of talin-2 is upregulated during differentiation; ectopic expression of talin-2 in undifferentiated myoblasts dysregulates the actin cytoskeleton, demonstrating that the timing of talin-2 expression during development is critical. In mature cardiomyocytes and skeletal muscle, talin-2 is expressed at costameres and intercalated discs, thus demonstrating that talin2 links integrins and the actin cytoskeleton in stable adhesion complexes involving mature sarcomeres.[6][9] Talin-2 appears to play a role in skeletal muscle development; specifically, in myoblast fusion, sarcomere assembly, and the integrity of myotendinous junctions. Ablation of both talin isoforms, talin-2 and talin-1 prevented normal myoblast fusion and sarcomere assembly, as well as assembly of integrin adhesion complexes, which was attributed to disrupted interactions between integrins and the actin cytoskeleton.[10] The mRNA expression of talin-2 has been shown to be regulated by the muscle-specific fragile X mental retardation, autosomal homolog 1 (FXR1) protein, which binds talin2 mRNAs directly and represses translation. Knockout of FXR1 upregulates talin-2 protein, which disrupts the architecture of desmosomes and costameres in cardiac muscle.[11]
Talin-2, like talin-1 appears to join ligand-bound integrins and the actin cytoskeleton, which enhances the affinity of integrins for the extracellular matrix and catalyzes focal adhesion-dependent signaling pathways,[12] as well as reinforces the cytoskeletal-integrin structure in response to an applied force.[13] The strength of the interaction between talin and integrin appears to be fine-tuned through differential expression of isoforms in different tissues. The talin-2/β1D-integrin isoforms that are expressed and colocalize in striated muscle form a markedly strong interaction, and a few amino acid deletions in the β1-integrin tail can alter this interaction by 1000-fold.[14]
Talin-2 is found within the neuronal synaptic region in brain tissue, and plays a role in clathrin-mediated endocytosis, coordinating phosphatidylinositol synthesis, and modulating actin dynamics through interactions with PIP kinase type 1γ, the major phosphatidylinositol 4,5-bisphosphate-synthesizing enzyme of the brain.[15]
Clinical significance
In patients with temporal lobe epilepsy, talin-2 protein was detected in cerebrospinal fluid, whereas expression was absent in non-epileptic patients.[16] Furthermore, postencephalitic epilepsy patients that were refractory to drug treatment exhibited markedly elevated levels of talin-2 protein in cerebrospinal fluid and reciprocally decreased levels in serum.[17] These data suggest that talin-2 may prove useful as a biomarker for epilepsy, and may be pathologically linked to this disease.
Studies have also shown that TLN2 is a direct target of miR-132, which is epigenetically silenced in prostate cancer,[18] suggesting that talin-2 may play a role in modulating cell adhesion in prostate cancer.
Interactions
TLN2 has been shown to interact with:
References
- ↑ "Entrez Gene: Talin 2". https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=83660.
- ↑ "Protein sequence of human TLN2 (Uniprot ID: Q9Y4G6)". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q9Y4G6.
- ↑ 3.0 3.1 "Analysis of the mammalian talin2 gene TLN2". Biochemical and Biophysical Research Communications 286 (5): 880–5. Sep 2001. doi:10.1006/bbrc.2001.5497. PMID 11527381.
- ↑ "New isoform-specific monoclonal antibodies reveal different sub-cellular localisations for talin1 and talin2". European Journal of Cell Biology 91 (3): 180–91. Mar 2012. doi:10.1016/j.ejcb.2011.12.003. PMID 22306379.
- ↑ "The N-terminal half of talin2 is sufficient for mouse development and survival". Biochemical and Biophysical Research Communications 337 (2): 670–6. Nov 2005. doi:10.1016/j.bbrc.2005.09.100. PMID 16202389.
- ↑ 6.0 6.1 "Talin2 is induced during striated muscle differentiation and is targeted to stable adhesion complexes in mature muscle". Cell Motility and the Cytoskeleton 64 (3): 157–73. Mar 2007. doi:10.1002/cm.20173. PMID 17183545.
- ↑ "Talin 2 is a large and complex gene encoding multiple transcripts and protein isoforms". The FEBS Journal 276 (6): 1610–28. Mar 2009. doi:10.1111/j.1742-4658.2009.06893.x. PMID 19220457.
- ↑ "Talin contains a C-terminal calpain2 cleavage site important in focal adhesion dynamics". PLOS ONE 7 (4): e34461. 2012. doi:10.1371/journal.pone.0034461. PMID 22496808.
- ↑ "Talin1 has unique expression versus talin 2 in the heart and modifies the hypertrophic response to pressure overload". The Journal of Biological Chemistry 288 (6): 4252–64. Feb 2013. doi:10.1074/jbc.M112.427484. PMID 23266827.
- ↑ "Talin 1 and 2 are required for myoblast fusion, sarcomere assembly and the maintenance of myotendinous junctions". Development 136 (21): 3597–606. Nov 2009. doi:10.1242/dev.035857. PMID 19793892.
- ↑ "Desmoplakin and talin2 are novel mRNA targets of fragile X-related protein-1 in cardiac muscle". Circulation Research 109 (3): 262–71. Jul 2011. doi:10.1161/CIRCRESAHA.111.244244. PMID 21659647.
- ↑ "Talin depletion reveals independence of initial cell spreading from integrin activation and traction". Nature Cell Biology 10 (9): 1062–8. Sep 2008. doi:10.1038/ncb1765. PMID 19160486.
- ↑ "Clustering of alpha(5)beta(1) integrins determines adhesion strength whereas alpha(v)beta(3) and talin enable mechanotransduction". Proceedings of the National Academy of Sciences of the United States of America 106 (38): 16245–50. Sep 2009. doi:10.1073/pnas.0902818106. PMID 19805288.
- ↑ "Structural diversity in integrin/talin interactions". Structure 18 (12): 1654–66. Dec 2010. doi:10.1016/j.str.2010.09.018. PMID 21134644.
- ↑ "A role for talin in presynaptic function". The Journal of Cell Biology 167 (1): 43–50. Oct 2004. doi:10.1083/jcb.200406020. PMID 15479735.
- ↑ "Proteomic analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy". Brain Research 1255: 180–9. Feb 2009. doi:10.1016/j.brainres.2008.12.008. PMID 19109932.
- ↑ "Talin 2 concentrations in cerebrospinal fluid in patients with epilepsy". Clinical Biochemistry 43 (13–14): 1129–32. Sep 2010. doi:10.1016/j.clinbiochem.2010.06.015. PMID 20620133.
- ↑ "DNA methylation silences miR-132 in prostate cancer". Oncogene 32 (1): 127–34. Jan 2013. doi:10.1038/onc.2012.14. PMID 22310291.
- ↑ "Talin contains three actin-binding sites each of which is adjacent to a vinculin-binding site". Journal of Cell Science 109 (11): 2715–26. Nov 1996. doi:10.1242/jcs.109.11.2715. PMID 8937989. https://figshare.com/articles/journal_contribution/Talin_contains_three_actin-binding_sites_each_of_which_is_adjacent_to_a_vinculin-binding_site_/10165394.
- ↑ "Identification of a talin-binding site in the integrin beta(3) subunit distinct from the NPLY regulatory motif of post-ligand binding functions. The talin n-terminal head domain interacts with the membrane-proximal region of the beta(3) cytoplasmic tail". The Journal of Biological Chemistry 274 (40): 28575–83. Oct 1999. doi:10.1074/jbc.274.40.28575. PMID 10497223.
- ↑ "The phosphotyrosine binding-like domain of talin activates integrins". The Journal of Biological Chemistry 277 (24): 21749–58. Jun 2002. doi:10.1074/jbc.M111996200. PMID 11932255.
- ↑ "The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation". The Journal of Biological Chemistry 274 (40): 28071–4. Oct 1999. doi:10.1074/jbc.274.40.28071. PMID 10497155.
- ↑ "Layilin, a novel talin-binding transmembrane protein homologous with C-type lectins, is localized in membrane ruffles". The Journal of Cell Biology 143 (2): 429–42. Oct 1998. doi:10.1083/jcb.143.2.429. PMID 9786953.
- ↑ "Structural basis for the interaction between the cytoplasmic domain of the hyaluronate receptor layilin and the talin F3 subdomain". Journal of Molecular Biology 382 (1): 112–26. Sep 2008. doi:10.1016/j.jmb.2008.06.087. PMID 18638481.
- ↑ "Interaction of focal adhesion kinase with cytoskeletal protein talin". The Journal of Biological Chemistry 270 (28): 16995–9. Jul 1995. doi:10.1074/jbc.270.28.16995. PMID 7622520.
- ↑ "Differential regulation of Pyk2 and focal adhesion kinase (FAK). The C-terminal domain of FAK confers response to cell adhesion". The Journal of Biological Chemistry 273 (4): 2384–9. Jan 1998. doi:10.1074/jbc.273.4.2384. PMID 9442086.
Further reading
- "Structural diversity in integrin/talin interactions". Structure 18 (12): 1654–66. Dec 2010. doi:10.1016/j.str.2010.09.018. PMID 21134644.
- "Organization of focal adhesion plaques is disrupted by action of the HIV-1 protease". Cell Biology International 26 (6): 529–39. 2002. doi:10.1006/cbir.2002.0895. PMID 12119179.
- "Integrin-mediated cell adhesion: the cytoskeletal connection". Biochemical Society Symposium 65: 79–99. 1999. PMID 10320934.
- "Recruitment and regulation of phosphatidylinositol phosphate kinase type 1 gamma by the FERM domain of talin". Nature 420 (6911): 85–9. Nov 2002. doi:10.1038/nature01147. PMID 12422219.
- "Vinculin and talin: focus on the myocardium". Journal of Investigative Medicine 57 (8): 849–55. Dec 2009. doi:10.2310/jim.0b013e3181c5e074. PMID 19952892.
- "Type I gamma phosphatidylinositol phosphate kinase targets and regulates focal adhesions". Nature 420 (6911): 89–93. Nov 2002. doi:10.1038/nature01082. PMID 12422220.
- "Proteomic analysis of cerebrospinal fluid from patients with idiopathic temporal lobe epilepsy". Brain Research 1255: 180–9. Feb 2009. doi:10.1016/j.brainres.2008.12.008. PMID 19109932.
- "Cytoskeletal proteins talin and vinculin in integrin-mediated adhesion". Biochemical Society Transactions 32 (Pt 5): 831–6. Nov 2004. doi:10.1042/BST0320831. PMID 15494027.
- "Cutting edge: differential segregation of the SRC homology 2-containing protein tyrosine phosphatase-1 within the early NK cell immune synapse distinguishes noncytolytic from cytolytic interactions". Journal of Immunology 168 (7): 3150–4. Apr 2002. doi:10.4049/jimmunol.168.7.3150. PMID 11907066.