# ELK1

## Overview
ELK1 is a gene that encodes the ETS transcription factor ELK1, a member of the ETS family of transcription factors. This protein is characterized by its ETS domain, which is crucial for DNA binding and is involved in regulating gene expression in response to extracellular signals. ELK1 functions primarily as a transcriptional activator within the MAPK/ERK signaling pathway, influencing the expression of immediate early genes such as c-fos. The protein's activity is modulated through phosphorylation by MAP kinases, which enhances its ability to form a ternary complex with the serum response factor (SRF) on the serum response element (SRE) of target genes. ELK1 plays a significant role in cellular processes such as growth, differentiation, and survival, and its dysregulation has been implicated in various diseases, including idiopathic pulmonary fibrosis, neurodegenerative disorders, and systemic lupus erythematosus (Sharma2010A; Janknecht1993Activation; Gille1995ERK; Sakurai2013Preferential; Tatler2016Reduced).

## Structure
The ELK1 protein is a member of the ETS family of transcription factors, characterized by its ETS domain, which is essential for DNA binding. This domain exhibits an α/β architecture with three α-helices and four antiparallel β-strands, forming a 'winged helix-turn-helix' (wHTH) topology. The α3 helix is crucial for DNA recognition, embedding itself in the major groove of DNA and interacting specifically with the GGA core sequence (Marmorstein2000StructureoftheElk1–DNAcomplexrevealshowDNAdistalresiduesaffectETSdomainrecognitionofDNA).

The B-box domain of ELK1 is involved in protein-protein interactions, particularly with the serum response factor (SRF). This domain forms an inducible α-helix, with key hydrophobic residues such as Y153, Y159, F162, and I164 playing significant roles in the interaction with SRF (Ling1997Molecular).

ELK1 can form a ternary complex with SRF and the serum response element (SRE), requiring both the ETS domain and additional sequences up to amino acid 169 for this interaction (Janknecht1992Elk1). The protein's structure is further stabilized by specific residues, such as Asp 69, which influence DNA binding affinity and specificity (Marmorstein2000StructureoftheElk1–DNAcomplexrevealshowDNAdistalresiduesaffectETSdomainrecognitionofDNA). 

Post-translational modifications, such as phosphorylation, are crucial for ELK1's activation, although specific details are not provided in the context.

## Function
ELK1 is a transcription factor that plays a pivotal role in regulating gene expression in response to extracellular signals, particularly through the MAPK/ERK signaling pathway. In healthy human cells, ELK1 is primarily involved in the transcriptional activation of immediate early genes such as c-fos, which are crucial for cellular responses to mitogenic and stress signals (Gille1995ERK; Yang2002The). ELK1 functions by forming a ternary complex with the serum response factor (SRF) on the serum response element (SRE) of target genes. This complex formation is enhanced by phosphorylation of ELK1 by MAP kinases, including ERK1/2, JNK, and p38, which increases its transactivation potential (Janknecht1993Activation; Besnard2011Elk-1).

Phosphorylation of ELK1 occurs at specific serine residues, such as S383 and S389, which are critical for its transcriptional activity (Thiel2021Critical). This phosphorylation induces a conformational change in ELK1, facilitating its DNA binding and interaction with coactivators, thereby promoting gene transcription (Yang1999The). ELK1 is predominantly active in the nucleus, where it influences transcriptional activity by modulating the expression of genes involved in cell growth, differentiation, and survival (Kasza2013Signaldependent). The dynamic regulation of ELK1 through phosphorylation and SUMOylation ensures precise control of gene expression in response to external stimuli (Yang2003Dynamic).

## Clinical Significance
Alterations in the expression or function of the ELK1 gene have been implicated in several diseases. In idiopathic pulmonary fibrosis (IPF), ELK1 acts as a repressor of the ITGB6 gene, which encodes the αvβ6 integrin. Reduced ELK1 expression leads to increased ITGB6 levels, contributing to the development and progression of lung fibrosis (Tatler2016Reduced). ELK1 deficiency in mice results in spontaneous fibrosis in the lungs and liver, highlighting its protective role against tissue fibrosis (Cairns2020Loss).

In neurodegenerative diseases, a specific phosphoform of Elk-1, phosphorylated at T417, is associated with neuronal inclusions in conditions such as Lewy body disease, Alzheimer's disease, and Huntington's disease. This phosphoform is linked to regionalized neuronal death, suggesting a role in disease pathogenesis (Sharma2010A). In Huntington's disease, Elk-1 is involved in early transcriptional changes, and its overexpression has been shown to alleviate transcriptional dysregulation and reduce mutant Huntingtin toxicity, indicating its potential as a therapeutic target (Yildirim2019Early).

In systemic lupus erythematosus (SLE), Elk-1 preferentially binds to a risk allele in the IL10 gene, upregulating IL-10 expression and contributing to disease activity (Sakurai2013Preferential).

## Interactions
ELK1 is a transcription factor that interacts with DNA and other proteins to regulate gene expression. It binds to specific DNA sequences through its ETS domain, which is necessary and sufficient for direct DNA-binding activity (Janknecht1992Elk1). ELK1 can form a ternary complex with the serum response factor (SRF) on the serum response element (SRE) of target genes. This interaction involves both DNA-protein and protein-protein interactions, potentially leading to a conformational change in ELK1 that affects its DNA-binding specificity (Shore1995The; Janknecht1992Elk1).

The ELK1 protein also interacts with the E74 binding site (E74-BS), a natural target sequence, forming complexes as monomers (Janknecht1992Elk1). The interaction with SRF is facilitated by specific domains within ELK1, including the ETS domain and additional sequences up to amino acid 169, which are crucial for forming the ternary complex (Janknecht1992Elk1).

ELK1's DNA-binding properties are influenced by its electrostatic interactions, which are modulated by charged residues within its structure. These interactions are crucial for its function in recognizing specific DNA sequences and forming stable complexes (Vo2021Salt).


## References


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[2. (Sharma2010A) Anup Sharma, Linda M. Callahan, Jai-Yoon Sul, Tae Kyung Kim, Lindy Barrett, Minsun Kim, James M. Powers, Howard Federoff, and James Eberwine. A neurotoxic phosphoform of elk-1 associates with inclusions from multiple neurodegenerative diseases. PLoS ONE, 5(2):e9002, February 2010. URL: http://dx.doi.org/10.1371/journal.pone.0009002, doi:10.1371/journal.pone.0009002. This article has 26 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0009002)

[3. (Janknecht1993Activation) R. Janknecht, W.H. Ernst, V. Pingoud, and A. Nordheim. Activation of ternary complex factor elk-1 by map kinases. The EMBO Journal, 12(13):5097–5104, December 1993. URL: http://dx.doi.org/10.1002/j.1460-2075.1993.tb06204.x, doi:10.1002/j.1460-2075.1993.tb06204.x. This article has 434 citations.](https://doi.org/10.1002/j.1460-2075.1993.tb06204.x)

[4. (Gille1995ERK) H. Gille, M. Kortenjann, O. Thomae, C. Moomaw, C. Slaughter, M.H. Cobb, and P.E. Shaw. Erk phosphorylation potentiates elk-1-mediated ternary complex formation and transactivation. The EMBO Journal, 14(5):951–962, March 1995. URL: http://dx.doi.org/10.1002/j.1460-2075.1995.tb07076.x, doi:10.1002/j.1460-2075.1995.tb07076.x. This article has 523 citations.](https://doi.org/10.1002/j.1460-2075.1995.tb07076.x)

[5. (Marmorstein2000StructureoftheElk1–DNAcomplexrevealshowDNAdistalresiduesaffectETSdomainrecognitionofDNA) Ronen Marmorstein, Yi Mo, Benjamin Vaessen, and Karen Johnston. Structure of the elk-1–dna complex reveals how dna-distal residues affect ets domain recognition of dna. Nature Structural Biology, 7(4):292–297, April 2000. URL: http://dx.doi.org/10.1038/74055, doi:10.1038/74055. This article has 132 citations.](https://doi.org/10.1038/74055)

[6. (Ling1997Molecular) Yan Ling, Jeremy H. Lakey, Claire E. Roberts, and Andrew D. Sharrocks. Molecular characterization of the b-box protein-protein interaction motif of the ets-domain transcription factor elk-1. The EMBO Journal, 16(9):2431–2440, May 1997. URL: http://dx.doi.org/10.1093/emboj/16.9.2431, doi:10.1093/emboj/16.9.2431. This article has 56 citations.](https://doi.org/10.1093/emboj/16.9.2431)

[7. (Sakurai2013Preferential) Daisuke Sakurai, Jian Zhao, Yun Deng, Jennifer A. Kelly, Elizabeth E. Brown, John B. Harley, Sang-Cheol Bae, Marta E. Alarcόn-Riquelme, Jeffrey C. Edberg, Robert P. Kimberly, Rosalind Ramsey-Goldman, Michelle A. Petri, John D. Reveille, Luis M. Vilá, Graciela S. Alarcón, Kenneth M. Kaufman, Timothy J. Vyse, Chaim O. Jacob, Patrick M. Gaffney, Kathy Moser Sivils, Judith A. James, Diane L. Kamen, Gary S. Gilkeson, Timothy B. Niewold, Joan T. Merrill, R. Hal Scofield, Lindsey A. Criswell, Anne M. Stevens, Susan A. Boackle, Jae-Hoon Kim, Jiyoung Choi, Bernardo A. Pons-Estel, Barry I. Freedman, Juan-Manuel Anaya, Javier Martin, C. Yung Yu, Deh-Ming Chang, Yeong Wook Song, Carl D. Langefeld, Weiling Chen, Jennifer M. Grossman, Rita M. Cantor, Bevra H. Hahn, and Betty P. Tsao. Preferential binding to elk-1 by sle-associated il10 risk allele upregulates il10 expression. PLoS Genetics, 9(10):e1003870, October 2013. URL: http://dx.doi.org/10.1371/journal.pgen.1003870, doi:10.1371/journal.pgen.1003870. This article has 35 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1371/journal.pgen.1003870)

[8. (Kasza2013Signaldependent) Aneta Kasza. Signal-dependent elk-1 target genes involved in transcript processing and cell migration. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1829(10):1026–1033, October 2013. URL: http://dx.doi.org/10.1016/j.bbagrm.2013.05.004, doi:10.1016/j.bbagrm.2013.05.004. This article has 38 citations.](https://doi.org/10.1016/j.bbagrm.2013.05.004)

[9. (Cairns2020Loss) Jennifer T. Cairns, Anthony Habgood, Rochelle C. Edwards-Pritchard, Chitra Joseph, Alison E. John, Chloe Wilkinson, Iain D. Stewart, Jack Leslie, Burns C. Blaxall, Katalin Susztak, Siegfried Alberti, Alfred Nordheim, Fiona Oakley, Gisli Jenkins, and Amanda L. Tatler. Loss of elk1 has differential effects on age-dependent organ fibrosis. The International Journal of Biochemistry & Cell Biology, 120:105668, March 2020. URL: http://dx.doi.org/10.1016/j.biocel.2019.105668, doi:10.1016/j.biocel.2019.105668. This article has 12 citations.](https://doi.org/10.1016/j.biocel.2019.105668)

[10. (Shore1995The) Paul Shore and Andrew D. Sharrocks. The ets-domain transcription factors elk-1 and sap-1 exhibit differential dna binding specifitoies. Nucleic Acids Research, 23(22):4698–4706, 1995. URL: http://dx.doi.org/10.1093/nar/23.22.4698, doi:10.1093/nar/23.22.4698. This article has 65 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/23.22.4698)

[11. (Yildirim2019Early) Ferah Yildirim, Christopher W. Ng, Vincent Kappes, Tobias Ehrenberger, Siobhan K. Rigby, Victoria Stivanello, Theresa A. Gipson, Anthony R. Soltis, Peter Vanhoutte, Jocelyne Caboche, David E. Housman, and Ernest Fraenkel. Early epigenomic and transcriptional changes reveal elk-1 transcription factor as a therapeutic target in huntington’s disease. Proceedings of the National Academy of Sciences, 116(49):24840–24851, November 2019. URL: http://dx.doi.org/10.1073/pnas.1908113116, doi:10.1073/pnas.1908113116. This article has 35 citations.](https://doi.org/10.1073/pnas.1908113116)

[12. (Yang2002The) Shen-Hsi Yang, Donna C. Bumpass, Neil D. Perkins, and Andrew D. Sharrocks. The ets domain transcription factor elk-1 contains a novel class of repression domain. Molecular and Cellular Biology, 22(14):5036–5046, July 2002. URL: http://dx.doi.org/10.1128/mcb.22.14.5036-5046.2002, doi:10.1128/mcb.22.14.5036-5046.2002. This article has 49 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.22.14.5036-5046.2002)

[13. (Besnard2011Elk-1) Antoine Besnard, Beatriz Galan-Rodriguez, Peter Vanhoutte, and Jocelyne Caboche. Elk-1 a transcription factor with multiple facets in the brain. Frontiers in Neuroscience, 2011. URL: http://dx.doi.org/10.3389/fnins.2011.00035, doi:10.3389/fnins.2011.00035. This article has 223 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fnins.2011.00035)

[14. (Vo2021Salt) Tam D. Vo, Amelia L. Schneider, W. David Wilson, and Gregory M. K. Poon. Salt bridge dynamics in protein/dna recognition: a comparative analysis of elk1 and etv6. Physical Chemistry Chemical Physics, 23(24):13490–13502, 2021. URL: http://dx.doi.org/10.1039/d1cp01568k, doi:10.1039/d1cp01568k. This article has 3 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1039/d1cp01568k)

[15. (Tatler2016Reduced) Amanda L. Tatler, Anthony Habgood, Joanne Porte, Alison E. John, Anastasios Stavrou, Emily Hodge, Cheryl Kerama-Likoko, Shelia M. Violette, Paul H. Weinreb, Alan J. Knox, Geoffrey Laurent, Helen Parfrey, Paul John Wolters, William Wallace, Siegfried Alberti, Alfred Nordheim, and Gisli Jenkins. Reduced ets domain-containing protein elk1 promotes pulmonary fibrosis via increased integrin αvβ6 expression. Journal of Biological Chemistry, 291(18):9540–9553, April 2016. URL: http://dx.doi.org/10.1074/jbc.m115.692368, doi:10.1074/jbc.m115.692368. This article has 30 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m115.692368)

[16. (Yang1999The) S.-H. Yang. The mechanism of phosphorylation-inducible activation of the ets-domain transcription factor elk-1. The EMBO Journal, 18(20):5666–5674, October 1999. URL: http://dx.doi.org/10.1093/emboj/18.20.5666, doi:10.1093/emboj/18.20.5666. This article has 93 citations.](https://doi.org/10.1093/emboj/18.20.5666)

[17. (Janknecht1992Elk1) Ralf Janknecht and Alfred Nordheim. Elk-1 protein domains required for direct and srf-assisted dna-binding. Nucleic Acids Research, 20(13):3317–3324, 1992. URL: http://dx.doi.org/10.1093/nar/20.13.3317, doi:10.1093/nar/20.13.3317. This article has 101 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1093/nar/20.13.3317)

[18. (Thiel2021Critical) Gerald Thiel, Tobias M. Backes, Lisbeth A. Guethlein, and Oliver G. Rössler. Critical protein–protein interactions determine the biological activity of elk-1, a master regulator of stimulus-induced gene transcription. Molecules, 26(20):6125, October 2021. URL: http://dx.doi.org/10.3390/molecules26206125, doi:10.3390/molecules26206125. This article has 6 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/molecules26206125)