5f28
From Proteopedia
(Difference between revisions)
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==Crystal structure of FAT domain of Focal Adhesion Kinase (FAK) bound to the transcription factor MEF2C== | ==Crystal structure of FAT domain of Focal Adhesion Kinase (FAK) bound to the transcription factor MEF2C== | ||
| - | <StructureSection load='5f28' size='340' side='right' caption='[[5f28]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='5f28' size='340' side='right'caption='[[5f28]], [[Resolution|resolution]] 2.90Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5f28]] is a 7 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F28 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5F28 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5f28]] is a 7 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F28 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5F28 FirstGlance]. <br> |
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5f28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f28 OCA], [http://pdbe.org/5f28 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5f28 RCSB], [http://www.ebi.ac.uk/pdbsum/5f28 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5f28 ProSAT]</span></td></tr> | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5f28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f28 OCA], [http://pdbe.org/5f28 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5f28 RCSB], [http://www.ebi.ac.uk/pdbsum/5f28 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5f28 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/MEF2C_MOUSE 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]<ref>PMID:18086704</ref> <ref>PMID:18438409</ref> <ref>PMID:18599437</ref> <ref>PMID:18599438</ref> <ref>PMID:19211936</ref> <ref>PMID:9162005</ref> <ref>PMID:9778514</ref> [[http://www.uniprot.org/uniprot/FAK1_MOUSE FAK1_MOUSE]] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 9 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription (By similarity).<ref>PMID:7997267</ref> <ref>PMID:7478517</ref> <ref>PMID:9148935</ref> <ref>PMID:10373530</ref> <ref>PMID:10806474</ref> <ref>PMID:11278462</ref> <ref>PMID:11369769</ref> <ref>PMID:12941275</ref> <ref>PMID:12702722</ref> <ref>PMID:15967814</ref> <ref>PMID:16000375</ref> <ref>PMID:16391003</ref> <ref>PMID:17093062</ref> <ref>PMID:18206965</ref> <ref>PMID:19473962</ref> <ref>PMID:19147981</ref> <ref>PMID:22056317</ref> | [[http://www.uniprot.org/uniprot/MEF2C_MOUSE 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]<ref>PMID:18086704</ref> <ref>PMID:18438409</ref> <ref>PMID:18599437</ref> <ref>PMID:18599438</ref> <ref>PMID:19211936</ref> <ref>PMID:9162005</ref> <ref>PMID:9778514</ref> [[http://www.uniprot.org/uniprot/FAK1_MOUSE FAK1_MOUSE]] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 9 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription (By similarity).<ref>PMID:7997267</ref> <ref>PMID:7478517</ref> <ref>PMID:9148935</ref> <ref>PMID:10373530</ref> <ref>PMID:10806474</ref> <ref>PMID:11278462</ref> <ref>PMID:11369769</ref> <ref>PMID:12941275</ref> <ref>PMID:12702722</ref> <ref>PMID:15967814</ref> <ref>PMID:16000375</ref> <ref>PMID:16391003</ref> <ref>PMID:17093062</ref> <ref>PMID:18206965</ref> <ref>PMID:19473962</ref> <ref>PMID:19147981</ref> <ref>PMID:22056317</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:27427476</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5f28" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Focal adhesion kinase|Focal adhesion kinase]] | ||
| + | *[[Myocyte enhancer factor 2|Myocyte enhancer factor 2]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Lk3 transgenic mice]] | ||
[[Category: Ambrosio, A L.B]] | [[Category: Ambrosio, A L.B]] | ||
[[Category: Cardoso, A C]] | [[Category: Cardoso, A C]] | ||
Revision as of 06:21, 17 April 2019
Crystal structure of FAT domain of Focal Adhesion Kinase (FAK) bound to the transcription factor MEF2C
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