Proteopedia

5f28

Crystal structure of FAT domain of Focal Adhesion Kinase (FAK) bound to the transcription factor MEF2CCrystal structure of FAT domain of Focal Adhesion Kinase (FAK) bound to the transcription factor MEF2C

Structural highlights

5f28 is a 7 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.9Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MEF2C_MOUSE Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle-specific genes. Controls cardiac morphogenesis and myogenesis, and is also involved in vascular development. May also be involved in neurogenesis and in the development of cortical architecture. Isoform 3 and isoform 4, which lack the repressor domain, are more active than isoform 1, isoform 2 and isoform 5 (By similarity). Plays an essential role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. Crucial for normal neuronal development, distribution, and electrical activity in the neocortex. Necessary for proper development of megakaryocytes and platelets and for bone marrow B-lymphopoiesis. Required for B-cell survival and proliferation in response to BCR stimulation, efficient IgG1 antibody responses to T-cell-dependent antigens and for normal induction of germinal center B-cells.[UniProtKB:Q06413][1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

Focal adhesion kinase (FAK) has emerged as a mediator of mechanotransduction in cardiomyocytes, regulating gene expression during hypertrophic remodeling. However, how FAK signaling is relayed onward to the nucleus is unclear. Here, we show that FAK interacts with and regulates myocyte enhancer factor 2 (MEF2), a master cardiac transcriptional regulator. In cardiomyocytes exposed to biomechanical stimulation, FAK accumulates in the nucleus, binds to and upregulates the transcriptional activity of MEF2 through an interaction with the FAK focal adhesion targeting (FAT) domain. In the crystal structure (2.9 A resolution), FAT binds to a stably folded groove in the MEF2 dimer, known to interact with regulatory cofactors. FAK cooperates with MEF2 to enhance the expression of Jun in cardiomyocytes, an important component of hypertrophic response to mechanical stress. These findings underscore a connection between the mechanotransduction involving FAK and transcriptional regulation by MEF2, with potential relevance to the pathogenesis of cardiac disease.

FAK Forms a Complex with MEF2 to Couple Biomechanical Signaling to Transcription in Cardiomyocytes.,Cardoso AC, Pereira AHM, Ambrosio ALB, Consonni SR, Rocha de Oliveira R, Bajgelman MC, Dias SMG, Franchini KG Structure. 2016 Aug 2;24(8):1301-1310. doi: 10.1016/j.str.2016.06.003. Epub 2016 , Jul 14. PMID:27427476[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Angelelli C, Magli A, Ferrari D, Ganassi M, Matafora V, Parise F, Razzini G, Bachi A, Ferrari S, Molinari S. Differentiation-dependent lysine 4 acetylation enhances MEF2C binding to DNA in skeletal muscle cells. Nucleic Acids Res. 2008 Feb;36(3):915-28. Epub 2007 Dec 17. PMID:18086704 doi:http://dx.doi.org/gkm1114
  2. ↑ Wilker PR, Kohyama M, Sandau MM, Albring JC, Nakagawa O, Schwarz JJ, Murphy KM. Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation. Nat Immunol. 2008 Jun;9(6):603-12. doi: 10.1038/ni.1609. Epub 2008 Apr 27. PMID:18438409 doi:http://dx.doi.org/10.1038/ni.1609
  3. ↑ Li H, Radford JC, Ragusa MJ, Shea KL, McKercher SR, Zaremba JD, Soussou W, Nie Z, Kang YJ, Nakanishi N, Okamoto S, Roberts AJ, Schwarz JJ, Lipton SA. Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9397-402. doi:, 10.1073/pnas.0802876105. Epub 2008 Jul 1. PMID:18599437 doi:http://dx.doi.org/10.1073/pnas.0802876105
  4. ↑ Barbosa AC, Kim MS, Ertunc M, Adachi M, Nelson ED, McAnally J, Richardson JA, Kavalali ET, Monteggia LM, Bassel-Duby R, Olson EN. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9391-6. doi:, 10.1073/pnas.0802679105. Epub 2008 Jul 1. PMID:18599438 doi:http://dx.doi.org/10.1073/pnas.0802679105
  5. ↑ Gekas C, Rhodes KE, Gereige LM, Helgadottir H, Ferrari R, Kurdistani SK, Montecino-Rodriguez E, Bassel-Duby R, Olson E, Krivtsov AV, Armstrong S, Orkin SH, Pellegrini M, Mikkola HK. Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis. Blood. 2009 Apr 9;113(15):3461-71. doi: 10.1182/blood-2008-07-167577. Epub 2009, Feb 11. PMID:19211936 doi:http://dx.doi.org/10.1182/blood-2008-07-167577
  6. ↑ Lin Q, Schwarz J, Bucana C, Olson EN. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science. 1997 May 30;276(5317):1404-7. PMID:9162005
  7. ↑ Lin Q, Lu J, Yanagisawa H, Webb R, Lyons GE, Richardson JA, Olson EN. Requirement of the MADS-box transcription factor MEF2C for vascular development. Development. 1998 Nov;125(22):4565-74. PMID:9778514
  8. ↑ Cardoso AC, Pereira AHM, Ambrosio ALB, Consonni SR, Rocha de Oliveira R, Bajgelman MC, Dias SMG, Franchini KG. FAK Forms a Complex with MEF2 to Couple Biomechanical Signaling to Transcription in Cardiomyocytes. Structure. 2016 Aug 2;24(8):1301-1310. doi: 10.1016/j.str.2016.06.003. Epub 2016 , Jul 14. PMID:27427476 doi:http://dx.doi.org/10.1016/j.str.2016.06.003

5f28, resolution 2.90Å

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