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6mpx
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<StructureSection load='6mpx' size='340' side='right'caption='[[6mpx]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='6mpx' size='340' side='right'caption='[[6mpx]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[6mpx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MPX OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6mpx]] 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=6MPX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MPX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=P6G:HEXAETHYLENE+GLYCOL'>P6G</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=6mpx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mpx OCA], [https://pdbe.org/6mpx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mpx RCSB], [https://www.ebi.ac.uk/pdbsum/6mpx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mpx ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
| - | [ | + | [https://www.uniprot.org/uniprot/CO4A1_HUMAN CO4A1_HUMAN] Defects in COL4A1 are a cause of brain small vessel disease with hemorrhage (BSVDH) [MIM:[https://omim.org/entry/607595 607595]. Brain small vessel diseases underlie 20 to 30 percent of ischemic strokes and a larger proportion of intracerebral hemorrhages. Inheritance is autosomal dominant.<ref>PMID:16598045</ref> <ref>PMID:17696175</ref> <ref>PMID:17379824</ref> <ref>PMID:20385946</ref> <ref>PMID:19477666</ref> Defects in COL4A1 are the cause of hereditary angiopathy with nephropathy aneurysms and muscle cramps (HANAC) [MIM:[https://omim.org/entry/611773 611773]. The clinical renal manifestations include hematuria and bilateral large cysts. Histologic analysis revealed complex basement membrane defects in kidney and skin. The systemic angiopathy appears to affect both small vessels and large arteries.<ref>PMID:18160688</ref> <ref>PMID:20818663</ref> Defects in COL4A1 are a cause of familial porencephaly (POREN1) [MIM:[https://omim.org/entry/175780 175780]. Porencephaly is a term used for any cavitation or cerebrospinal fluid-filled cyst in the brain. Porencephaly type 1 is usually unilateral and results from focal destructive lesions such as fetal vascular occlusion or birth trauma. Type 2, or schizencephalic porencephaly, is usually symmetric and represents a primary defect or arrest in the development of the cerebral ventricles.<ref>PMID:15905400</ref> <ref>PMID:16107487</ref> <ref>PMID:19194877</ref> [https://www.uniprot.org/uniprot/CO4A2_HUMAN CO4A2_HUMAN] Defects in COL4A2 are the cause of porencephaly type 2 (POREN2) [MIM:[https://omim.org/entry/614483 614483]. POREN2 is a neurologic disorder characterized by a fluid-filled cysts or cavities within the cerebral hemispheres. Affected individuals typically have hemiplegia, seizures, and intellectual disability. Porencephaly type 2, or schizencephalic porencephaly, is usually symmetric and represents a primary defect in the development of the cerebral ventricles.<ref>PMID:22209246</ref> Defects in COL4A2 are a cause of susceptibility to intracerebral hemorrhage (ICH) [MIM:[https://omim.org/entry/614519 614519]. ICH is a pathological condition characterized by bleeding into one or both cerebral hemispheres including the basal ganglia and the cerebral cortex. It is often associated with hypertension and craniocerebral trauma. Intracerebral bleeding is a common cause of stroke.<ref>PMID:22209247</ref> |
== Function == | == Function == | ||
| - | [ | + | [https://www.uniprot.org/uniprot/CO4A1_HUMAN CO4A1_HUMAN] Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.<ref>PMID:10811134</ref> <ref>PMID:16481288</ref> <ref>PMID:16151532</ref> <ref>PMID:18775695</ref> Arresten, comprising the C-terminal NC1 domain, inhibits angiogenesis and tumor formation. The C-terminal half is found to possess the anti-angiogenic activity. Specifically inhibits endothelial cell proliferation, migration and tube formation. Inhibits expression of hypoxia-inducible factor 1alpha and ERK1/2 and p38 MAPK activation. Ligand for alpha1/beta1 integrin.<ref>PMID:10811134</ref> <ref>PMID:16481288</ref> <ref>PMID:16151532</ref> <ref>PMID:18775695</ref> [https://www.uniprot.org/uniprot/CO4A2_HUMAN CO4A2_HUMAN] Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen.<ref>PMID:10625665</ref> <ref>PMID:12876280</ref> <ref>PMID:15899827</ref> Canstatin, a cleavage product corresponding to the collagen alpha 2(IV) NC1 domain, possesses both anti-angiogenic and anti-tumor cell activity. It inhibits proliferation and migration of endothelial cells, reduces mitochondrial membrane potential, and induces apoptosis. Specifically induces Fas-dependent apoptosis and activates procaspase-8 and -9 activity. Ligand for alphavbeta3 and alphavbeta5 integrins.<ref>PMID:10625665</ref> <ref>PMID:12876280</ref> <ref>PMID:15899827</ref> |
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Collagen IV scaffold is a principal component of the basement membrane (BM), a specialized extracellular matrix that is essential for animal multicellularity and tissue evolution. Scaffold assembly begins with the trimerization of alpha-chains into protomers inside the cell, which then are secreted and undergo oligomerization outside the cell. For the ubiquitous scaffold composed of alpha1 and alpha2 chains, both intracellular and extracellular stages are mediated by the non-collagenous domain (NC1). The association of protomers is chloride-dependent, whereby chloride ions induce interactions of protomers' trimeric NC1 domains leading to NC1 hexamer formation. Here, we investigated the mechanisms, kinetics, and functionality of the chloride ion-mediated protomer assembly by using a single-chain technology to produce a stable NC1 trimer comprising alpha1, alpha2, and alpha1 NC1 monomers. We observed that in the presence of chloride, the single-chain NC1 trimer self-assembles into a hexamer, for which the crystal structure was determined. We discovered that a chloride ring, comprising twelve ions, induces the assembly of and stabilizes the NC1 hexamer. Furthermore, we found that the chloride ring is evolutionarily conserved across all animals, first appearing in cnidarians. These findings reveal a fundamental role for the chloride ring in the assembly of collagen IV scaffolds of BMs, a critical event enabling tissue evolution and development. Moreover, the single-chain technology is foundational for generating trimeric NC1 domains of other alpha-chain compositions to investigate the alpha121, alpha345, and alpha565 collagen IV scaffolds and to develop therapies for managing Alport syndrome, Goodpasture's disease, and cancerous tumor growth. | ||
| + | |||
| + | A chloride ring is an ancient evolutionary innovation mediating the assembly of the collagen IV scaffold of basement membranes.,Pedchenko V, Bauer R, Pokidysheva EN, Al-Shaer A, Forde NR, Fidler AL, Hudson BG, Boudko SP J Biol Chem. 2019 Mar 28. pii: RA119.007426. doi: 10.1074/jbc.RA119.007426. PMID:30923125<ref>PMID:30923125</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6mpx" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Collagen 3D structures|Collagen 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Bauer | + | [[Category: Bauer R]] |
| - | [[Category: Boudko | + | [[Category: Boudko SP]] |
| - | [[Category: Hudson | + | [[Category: Hudson BG]] |
| - | + | ||
Current revision
Twelve chloride ions induce formation and stabilize the NC1 hexamer of collagen IV assembled from transition state trimers
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