5nax

Crystal structures of homooligomers of the non-collagenous domains of collagen type IV. alpha121NC1

spinqualitylabelsall models 5nax, resolution 2.82Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5nax is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.82Å Ligands: CL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease CO4A1_HUMAN Defects in COL4A1 are a cause of brain small vessel disease with hemorrhage (BSVDH) [MIM:607595. Brain small vessel diseases underlie 20 to 30 percent of ischemic strokes and a larger proportion of intracerebral hemorrhages. Inheritance is autosomal dominant. Defects in COL4A1 are the cause of hereditary angiopathy with nephropathy aneurysms and muscle cramps (HANAC) [MIM: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. Defects in COL4A1 are a cause of familial porencephaly (POREN1) [MIM: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. Function 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. 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. Publication Abstract from PubMed Basement membranes are extracellular structures of epithelia and endothelia that have collagen IV scaffolds of triple alpha-chain helical protomers that associate end-to-end, forming networks. The molecular mechanisms by which the noncollagenous C-terminal domains of alpha-chains direct the selection and assembly of the alpha1alpha2alpha1 and alpha3alpha4alpha5 hetero-oligomers found in vivo remain obscure. Autoantibodies against the noncollagenous domains of the alpha3alpha4alpha5 hexamer or mutations therein cause Goodpasture's or Alport's syndromes, respectively. To gain further insight into oligomer-assembly mechanisms as well as into Goodpasture's and Alport's syndromes, crystal structures of non-collagenous domains produced by recombinant methods were determined. The spontaneous formation of canonical homohexamers (dimers of trimers) of these domains of the alpha1, alpha3 and alpha5 chains was shown and the components of the Goodpasture's disease epitopes were viewed. Crystal structures of the alpha2 and alpha4 non-collagenous domains generated by recombinant methods were also determined. These domains spontaneously form homo-oligomers that deviate from the canonical architectures since they have a higher number of subunits (dimers of tetramers and of hexamers, respectively). Six flexible structural motifs largely explain the architectural variations. These findings provide insight into noncollagenous domain folding, while supporting the in vivo operation of extrinsic mechanisms for restricting the self-assembly of noncollagenous domains. Intriguingly, Alport's syndrome missense mutations concentrate within the core that nucleates the folding of the noncollagenous domain, suggesting that this syndrome, when owing to missense changes, is a folding disorder that is potentially amenable to pharmacochaperone therapy. Structures of collagen IV globular domains: insight into associated pathologies, folding and network assembly.,Casino P, Gozalbo-Rovira R, Rodriguez-Diaz J, Banerjee S, Boutaud A, Rubio V, Hudson BG, Saus J, Cervera J, Marina A IUCrJ. 2018 Oct 10;5(Pt 6):765-779. doi: 10.1107/S2052252518012459. eCollection, 2018 Nov 1. PMID:30443360 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Collagen 3D structures

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