Hundreds of variants in the COL4A3, COL4A4 and COL4A5 genes cause a broad range of glomerulopathies affecting the function of the glomerular basement membrane (GBM). These genes encode the assembly of collagen IV ?345 scaffolds, the major constituent of the GBM, the autoantigen in Goodpasture?s (GP) autoimmune disease, and the protein mutated in Alport syndrome and other genetic glomerulopathies. GP disease has and continues to serve as the vanguard for unlocking mysteries of the molecular structure of the ?345 scaffold and pathogenic mechanisms underlying both acquired and genetic glomerulopathies. Our overarching hypothesis is: Collagen IV ?345 scaffold tethers macromolecules forming supramolecular complexes and perturbation of scaffold causes glomerulopathies.
Four specific aims address key unanswered questions that are defined based on our previous and recent discoveries.
Aim 1 : ?345NC1 Hexamer. To determine the atomic structure of the ?345NC1 hexamer and mechanism of GP epitopes formation. The structure of the ?345NC1 hexamer, GP autoantigen, is unknown. We hypothesize that upon perturbation of quaternary structure of the non-immunogenic ?345NC1 hexamer, EA and EB regions undergo conformational changes forming pathogenic GP neoepitopes.
Aim 2 : ?3 Zurich Mutation. To determine the impact of ?3 Zurich mutation on GP epitopes formation. We found a mutation in ?3NC1 domain associated with the first case of familial GP disease, providing genetic evidence for a triggering mechanism. We hypothesize that the mutation causes structural perturbation of the EA and EB regions of ?3NC1, which can contribute to GP epitopes presentation.
Aim 3. Chloride ring. To determine role of chloride in assembly of the collagen IV ?345 scaffold and formation of GP epitopes. Whereas structure, assembly and functions of the ?121 scaffold has been successfully studied for over 40 years, our knowledge about the ?345 scaffold remains obscure. We demonstrated that chloride concentration is a critical factor in GP antibody binding. We hypothesize that assembly of the ?345NC1 hexamer, its stability and GP-reactivity is dependent on chloride ions.
Aim 4 : ?121 Supramolecular complexes. To characterize the supramolecular complexes of ?121 collagen IV within a basement membrane. We discovered a garland architecture of the ?121 scaffold coated with proteoglycans. This suprastructure is a potential core feature of basement membrane. We hypothesize that collagen IV ?121 scaffold tethers macromolecules forming distinct supramolecular complexes which enable basement membrane assembly. The achievement of the aims will yield new insights to the etiology of GP disease and the structure and assembly of collagen IV scaffolds, leading to a framework for development of novel therapeutic strategies for GBM diseases.
Kidney diseases such as Goodpasture?s disease, Alport syndrome and diabetic nephropathy damage the ultrafilter causing kidney failure. We study the molecular architecture and function of the collagen scaffolds that comprise the normal filter and which are damaged by these diseases. The knowledge gained provides a framework to develop new forms of therapy.
|McCall, A Scott; Bhave, Gautam; Pedchenko, Vadim et al. (2018) Inhibitory Anti-Peroxidasin Antibodies in Pulmonary-Renal Syndromes. J Am Soc Nephrol 29:2619-2625|
|Pedchenko, Vadim; Kitching, A Richard; Hudson, Billy G (2018) Goodpasture's autoimmune disease - A collagen IV disorder. Matrix Biol 71-72:240-249|
|Brown, Kyle L; Banerjee, Surajit; Feigley, Andrew et al. (2018) Salt-bridge modulates differential calcium-mediated ligand binding to integrin ?1- and ?2-I domains. Sci Rep 8:2916|
|Fidler, Aaron L; Boudko, Sergei P; Rokas, Antonis et al. (2018) The triple helix of collagens - an ancient protein structure that enabled animal multicellularity and tissue evolution. J Cell Sci 131:|
|Boudko, Sergei P; Danylevych, Neonila; Hudson, Billy G et al. (2018) Basement membrane collagen IV: Isolation of functional domains. Methods Cell Biol 143:171-185|
|Jones-Paris, Celestial R; Paria, Sayan; Berg, Taloa et al. (2017) Embryo implantation triggers dynamic spatiotemporal expression of the basement membrane toolkit during uterine reprogramming. Matrix Biol 57-58:347-365|
|Fidler, Aaron L; Darris, Carl E; Chetyrkin, Sergei V et al. (2017) Collagen IV and basement membrane at the evolutionary dawn of metazoan tissues. Elife 6:|
|Xie, Li-Jun; Cui, Zhao; Chen, Fang-Jin et al. (2017) The susceptible HLA class II alleles and their presenting epitope(s) in Goodpasture's disease. Immunology 151:395-404|
|Ooi, Joshua D; Petersen, Jan; Tan, Yu H et al. (2017) Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature 545:243-247|
|Cui, Zhao; Zhao, Ming-Hui; Jia, Xiao-Yu et al. (2016) Antibodies to ?5 chain of collagen IV are pathogenic in Goodpasture's disease. J Autoimmun 70:1-11|
Showing the most recent 10 out of 89 publications