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Collagen IVα345 dysfunction in glomerular basement membrane diseases. III. A functional framework for α345 hexamer
Vadim Pedchenko1, Sergei P Boudko2, Mary Barber3
1Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Center for Matrix Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
The Journal of Biological Chemistry
|March 29, 2021
Summary
Researchers discovered a genetic variant in collagen IV
Area of Science:
- Biochemistry
- Structural Biology
- Genetics
Background:
- Collagen IV is crucial for glomerular basement membrane structure.
- Genetic variants in collagen IV are linked to kidney diseases like Goodpasture's disease and Alport syndrome.
- The hexamer assembly mechanism of collagen IV's NC1 domain (α345) was previously unclear.
Purpose of the Study:
- To elucidate the mechanism of collagen IV hexamer assembly.
- To understand how genetic variants cause glomerular basement membrane diseases.
- To determine the crystal structure of the α345 hexamer.
Main Methods:
- In vitro assembly assays using α3, α4, and α5 NC1 monomers.
- Crystal structure determination of the α345 hexamer.
- Cell culture expression and characterization of recombinant α345 miniprotomers.
Main Results:
- Chloride ions induce specific in vitro hexamer assembly, stabilizing it with sulfilimine crosslinks.
- Chloride ion-dependent assembly reveals conformational plasticity in bioactive sites.
- In cells, NC1-directed trimerization occurs intracellularly, followed by extracellular hexamerization signaled by a chloride gradient.
Conclusions:
- The study reveals the detailed mechanism of collagen IV α345 hexamer assembly, including chloride ion and gradient roles.
- The crystal structure provides a framework for understanding disease-causing hexamer dysfunction.
- Restoring native conformation and hexamer replacement are potential therapeutic strategies for glomerular basement membrane diseases.
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