5nb1
Crystal structures of homooligomers of collagen type IV. alpha4NC1
Structural highlights
DiseaseCO4A4_HUMAN Benign familial hematuria;Autosomal dominant Alport syndrome;Autosomal recessive Alport syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionCO4A4_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. Publication Abstract from PubMedBasement 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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