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| | ==Specificity and Structure of a high affinity Activin-like 1 (ALK1) signaling complex== | | ==Specificity and Structure of a high affinity Activin-like 1 (ALK1) signaling complex== |
| - | <StructureSection load='4fao' size='340' side='right' caption='[[4fao]], [[Resolution|resolution]] 3.36Å' scene=''> | + | <StructureSection load='4fao' size='340' side='right'caption='[[4fao]], [[Resolution|resolution]] 3.36Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4fao]] is a 36 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4FAO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FAO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4fao]] is a 36 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=4FAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FAO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BMP9, GDF2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ACVRL1, ACVRLK1, ALK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ActRIIB, ACVR2B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4fao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fao OCA], [https://pdbe.org/4fao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fao RCSB], [https://www.ebi.ac.uk/pdbsum/4fao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fao ProSAT]</span></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=4fao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fao OCA], [http://pdbe.org/4fao PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fao RCSB], [http://www.ebi.ac.uk/pdbsum/4fao PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fao ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/AVR2B_HUMAN AVR2B_HUMAN]] Defects in ACVR2B are the cause of visceral heterotaxy autosomal type 4 (HTX4) [MIM:[http://omim.org/entry/613751 613751]]. A form of visceral heterotaxy, a complex disorder due to disruption of the normal left-right asymmetry of the thoracoabdominal organs. It results in an abnormal arrangement of visceral organs, and a wide variety of congenital defects. Clinical features of visceral heterotaxy type 4 include dextrocardia, right aortic arch and a right-sided spleen, anomalies of the inferior and the superior vena cava, atrial ventricular canal defect with dextro-transposed great arteries, pulmonary stenosis, polysplenia and midline liver.<ref>PMID:9916847</ref> [[http://www.uniprot.org/uniprot/ACVL1_HUMAN ACVL1_HUMAN]] Defects in ACVRL1 are the cause of hereditary hemorrhagic telangiectasia type 2 (HHT2) [MIM:[http://omim.org/entry/600376 600376]]; also known as Osler-Rendu-Weber syndrome 2 (ORW2). HHT2 is an autosomal dominant multisystemic vascular dysplasia, characterized by recurrent epistaxis, muco-cutaneous telangiectases, gastro-intestinal hemorrhage, and pulmonary, cerebral and hepatic arteriovenous malformations; all secondary manifestations of the underlying vascular dysplasia.<ref>PMID:9245985</ref> <ref>PMID:8640225</ref> <ref>PMID:10694922</ref> <ref>PMID:10767348</ref> <ref>PMID:11170071</ref> <ref>PMID:11484689</ref> <ref>PMID:14684682</ref> <ref>PMID:15024723</ref> <ref>PMID:15712270</ref> | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GDF2_HUMAN GDF2_HUMAN]] Potent circulating inhibitor of angiogenesis. Could be involved in bone formation. Signals through the type I activin receptor ACVRL1 but not other Alks.<ref>PMID:18309101</ref> <ref>PMID:22799562</ref> [[http://www.uniprot.org/uniprot/AVR2B_HUMAN AVR2B_HUMAN]] Transmembrane serine/threonine kinase activin type-2 receptor forming an activin receptor complex with activin type-1 serine/threonine kinase receptors (ACVR1, ACVR1B or ACVR1c). Transduces the activin signal from the cell surface to the cytoplasm and is thus regulating many physiological and pathological processes including neuronal differentiation and neuronal survival, hair follicle development and cycling, FSH production by the pituitary gland, wound healing, extracellular matrix production, immunosuppression and carcinogenesis. Activin is also thought to have a paracrine or autocrine role in follicular development in the ovary. Within the receptor complex, the type-2 receptors act as a primary activin receptors (binds activin-A/INHBA, activin-B/INHBB as well as inhibin-A/INHA-INHBA). The type-1 receptors like ACVR1B act as downstream transducers of activin signals. Activin binds to type-2 receptor at the plasma membrane and activates its serine-threonine kinase. The activated receptor type-2 then phosphorylates and activates the type-1 receptor. Once activated, the type-1 receptor binds and phosphorylates the SMAD proteins SMAD2 and SMAD3, on serine residues of the C-terminal tail. Soon after their association with the activin receptor and subsequent phosphorylation, SMAD2 and SMAD3 are released into the cytoplasm where they interact with the common partner SMAD4. This SMAD complex translocates into the nucleus where it mediates activin-induced transcription. Inhibitory SMAD7, which is recruited to ACVR1B through FKBP1A, can prevent the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. Activin signal transduction is also antagonized by the binding to the receptor of inhibin-B via the IGSF1 inhibin coreceptor.<ref>PMID:8622651</ref> [[http://www.uniprot.org/uniprot/ACVL1_HUMAN ACVL1_HUMAN]] Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. May bind activin as well.<ref>PMID:22799562</ref> <ref>PMID:22718755</ref> | + | [https://www.uniprot.org/uniprot/GDF2_HUMAN GDF2_HUMAN] Potent circulating inhibitor of angiogenesis. Could be involved in bone formation. Signals through the type I activin receptor ACVRL1 but not other Alks.<ref>PMID:18309101</ref> <ref>PMID:22799562</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Growth differentiation factor|Growth differentiation factor]] | + | *[[Growth differentiation factor 3D STRUCTURES|Growth differentiation factor 3D STRUCTURES]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Greppi, C]] | + | [[Category: Large Structures]] |
| - | [[Category: Grinberg, A V]] | + | [[Category: Greppi C]] |
| - | [[Category: Kumar, R]] | + | [[Category: Grinberg AV]] |
| - | [[Category: Liharska, K]] | + | [[Category: Kumar R]] |
| - | [[Category: Liu, J]] | + | [[Category: Liharska K]] |
| - | [[Category: Lowden, P]] | + | [[Category: Liu J]] |
| - | [[Category: Martinez-Hackert, E]] | + | [[Category: Lowden P]] |
| - | [[Category: Sako, D]] | + | [[Category: Martinez-Hackert E]] |
| - | [[Category: Seehra, J]] | + | [[Category: Sako D]] |
| - | [[Category: Townson, S A]] | + | [[Category: Seehra J]] |
| - | [[Category: Ucran, J A]] | + | [[Category: Townson SA]] |
| - | [[Category: Underwood, K W]] | + | [[Category: Ucran JA]] |
| - | [[Category: Ctk]]
| + | [[Category: Underwood KW]] |
| - | [[Category: Cystine knot]]
| + | |
| - | [[Category: Extracellular domain]]
| + | |
| - | [[Category: Receptor]]
| + | |
| - | [[Category: Signaling protein-signaling protein complex]]
| + | |
| - | [[Category: Tgf-beta]]
| + | |
| Structural highlights
Function
GDF2_HUMAN Potent circulating inhibitor of angiogenesis. Could be involved in bone formation. Signals through the type I activin receptor ACVRL1 but not other Alks.[1] [2]
Publication Abstract from PubMed
Activin receptor-like kinase 1 (ALK1), an endothelial cell specific type I receptor of the TGF-beta superfamily, is an important regulator of normal blood vessel development as well as pathological tumor angiogenesis. As such, ALK1 is an important therapeutic target. Thus, several ALK1 directed agents are currently in clinical trials as anti-angiogenic cancer therapeutics. Given the biological and clinical importance of the ALK1 signaling pathway, we sought to elucidate the biophysical and structural basis underlying ALK1 signaling. The TGF-beta family ligands BMP9 and BMP10 as well as the three type II TGF-beta family receptors ActRIIA, ActRIIB and BMPRII have been implicated in ALK1 signaling. Here, we provide a kinetic and thermodynamic analysis of BMP9 and BMP10 interactions with ALK1 and type II receptors. Our data show that BMP9 displays a significant discrimination in type II receptor binding, while BMP10 does not. We also report the crystal structure of a fully assembled ternary complex of BMP9 with the extracellular domains of ALK1 and ActRIIB. The structure reveals that the high specificity of ALK1 for BMP9/10 is determined by a novel orientation of ALK1 with respect to BMP9, which leads to a unique set of receptor-ligand interactions. In addition, the structure explains how BMP9 discriminates between low and high affinity type II receptors. Taken together, our findings provide structural and mechanistic insights into ALK1 signaling that could serve as a basis for novel anti-angiogenic therapies.
Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex.,Townson SA, Martinez-Hackert E, Greppi C, Lowden P, Sako D, Liu J, Ucran JA, Liharska K, Underwood KW, Seehra J, Kumar R, Grinberg AV J Biol Chem. 2012 Jun 20. PMID:22718755[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ David L, Mallet C, Keramidas M, Lamande N, Gasc JM, Dupuis-Girod S, Plauchu H, Feige JJ, Bailly S. Bone morphogenetic protein-9 is a circulating vascular quiescence factor. Circ Res. 2008 Apr 25;102(8):914-22. doi: 10.1161/CIRCRESAHA.107.165530. Epub, 2008 Feb 28. PMID:18309101 doi:10.1161/CIRCRESAHA.107.165530
- ↑ Mahlawat P, Ilangovan U, Biswas T, Sun LZ, Hinck AP. Structure of the Alk1 extracellular domain and characterization of its bone morphogenetic protein (BMP) binding properties. Biochemistry. 2012 Aug 14;51(32):6328-41. Epub 2012 Aug 2. PMID:22799562 doi:10.1021/bi300942x
- ↑ Townson SA, Martinez-Hackert E, Greppi C, Lowden P, Sako D, Liu J, Ucran JA, Liharska K, Underwood KW, Seehra J, Kumar R, Grinberg AV. Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex. J Biol Chem. 2012 Jun 20. PMID:22718755 doi:10.1074/jbc.M112.377960
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