3bea: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3bea]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BEA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BEA FirstGlance]. <br> | <table><tr><td colspan='2'>[[3bea]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BEA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BEA FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IXH:8-(2,3-DIHYDRO-1H-INDEN-5-YL)-2-({4-[(3R,5S)-3,5-DIMETHYLPIPERAZIN-1-YL]PHENYL}AMINO)-5-OXO-5,8-DIHYDROPYRIDO[2,3-D]PYRIMIDINE-6-CARBOXAMIDE'>IXH</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.02Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IXH:8-(2,3-DIHYDRO-1H-INDEN-5-YL)-2-({4-[(3R,5S)-3,5-DIMETHYLPIPERAZIN-1-YL]PHENYL}AMINO)-5-OXO-5,8-DIHYDROPYRIDO[2,3-D]PYRIMIDINE-6-CARBOXAMIDE'>IXH</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3bea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bea OCA], [https://pdbe.org/3bea PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bea RCSB], [https://www.ebi.ac.uk/pdbsum/3bea PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bea ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3bea FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bea OCA], [https://pdbe.org/3bea PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bea RCSB], [https://www.ebi.ac.uk/pdbsum/3bea PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bea ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
[https://www.uniprot.org/uniprot/CSF1R_HUMAN CSF1R_HUMAN] Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref> Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref> Defects in CSF1R are the cause of leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:[https://omim.org/entry/221820 221820]. An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref> <ref>PMID:22197934</ref> [https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] Defects in TEK are a cause of dominantly inherited venous malformations (VMCM) [MIM:[https://omim.org/entry/600195 600195]; an error of vascular morphogenesis characterized by dilated, serpiginous channels.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref> <ref>PMID:8980225</ref> <ref>PMID:10369874</ref> <ref>PMID:19888299</ref> Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.<ref>PMID:18366015</ref> <ref>PMID:20651738</ref> | |||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/CSF1R_HUMAN CSF1R_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor.<ref>PMID:7683918</ref> <ref>PMID:12882960</ref> <ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:16170366</ref> <ref>PMID:18467591</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:20489731</ref> <ref>PMID:20829061</ref> <ref>PMID:20504948</ref> <ref>PMID:16337366</ref> <ref>PMID:19193011</ref> [https://www.uniprot.org/uniprot/TIE2_HUMAN TIE2_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post-natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1.<ref>PMID:9204896</ref> <ref>PMID:12816861</ref> <ref>PMID:15284220</ref> <ref>PMID:14665640</ref> <ref>PMID:15851516</ref> <ref>PMID:18425120</ref> <ref>PMID:18425119</ref> <ref>PMID:19223473</ref> <ref>PMID:18366015</ref> <ref>PMID:20651738</ref> | |||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Schubert C]] | |||
[[Category: Schubert | |||