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Structures of collagen IV globular domains: insight into associated pathologies, folding and network assembly

DOI: 10.1107/S2052252518012459 DOI Help

Authors: Patricia Casino (Universitat de València; Consejo Superior de Investigaciones Científicas (IBV–CSIC)) , Roberto Gozalbo-rovira (Centro de Investigación Príncipe Felipe; Facultad de Medicina at Universitat de València) , Jesús Rodríguez-díaz (Centro de Investigación Príncipe Felipe; Universitat de València) , Sreedatta Banerjee (Center for Prostate Disease Research) , Ariel Boutaud (BioStratum Inc.) , Vicente Rubio (Consejo Superior de Investigaciones Científicas (IBV–CSIC)) , Billy G. Hudson (Vanderbilt University Medical Center) , Juan Saus (Universitat de València) , Javier Cervera (Consejo Superior de Investigaciones Científicas (IBV–CSIC); CIBER de Enfermedades Raras (CIBERER–ISCIII); Centro de Investigación Príncipe Felipe) , Alberto Marina (Consejo Superior de Investigaciones Científicas (IBV–CSIC); CIBER de Enfermedades Raras (CIBERER–ISCIII))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Iucrj , VOL 5

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 10121 , 14739

Open Access Open Access

Abstract: Basement membranes are extracellular structures of epithelia and endothelia that have collagen IV scaffolds of triple α-chain helical protomers that associate end-to-end, forming networks. The molecular mechanisms by which the noncollagenous C-terminal domains of α-chains direct the selection and assembly of the α1α2α1 and α3α4α5 hetero-oligomers found in vivo remain obscure. Autoantibodies against the noncollagenous domains of the α3α4α5 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 non­collagenous domains produced by recombinant methods were determined. The spontaneous formation of canonical homohexamers (dimers of trimers) of these domains of the α1, α3 and α5 chains was shown and the components of the Goodpasture's disease epitopes were viewed. Crystal structures of the α2 and α4 non­collagenous 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.

Journal Keywords: collagen type IV; network assembly; (IV)NC1 hexamers; Goodpasture's disease; Alport's syndrome

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ESRF; ALBA

Documents:
tj5018.pdf