Macromolecular assembly of polycystin-2 intracytosolic C-terminal domain

Mutations in PKD2 are responsible for approximately 15% of the autosomal dominant polycystic kidney disease cases. This gene encodes polycystin-2, a calcium-permeable cation channel whose C-terminal intracytosolic tail (PC2t) plays an important role in its interaction with a number of different prot...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-06, Vol.108 (24), p.9833-9838
Main Authors: Ferreira, Frederico M., Oliveira, Leandro C., Germino, Gregory G., Onuchic, José N., Onuchic, Luiz F.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Atoms & subatomic particles
Autosomal dominant polycystic kidney
Biological Sciences
Blotting, Western
Calcium
Calcium - chemistry
Calcium - metabolism
Circular Dichroism
Dichroism
Humans
Hydrophobic and Hydrophilic Interactions
Kidney diseases
Modeling
Models, Chemical
Models, Molecular
Molecular Sequence Data
Molecular Weight
Molecules
Monomers
Mutation
Oligomers
Polycystic kidney diseases
Protein Conformation
Protein Multimerization
Protein Structure, Secondary
Protein Structure, Tertiary
Proteins
Scattering, Small Angle
Simulation
Simulations
Superposition principle
Thermodynamics
TRPP Cation Channels - chemistry
TRPP Cation Channels - genetics
TRPP Cation Channels - metabolism
X-Ray Diffraction
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Summary:Mutations in PKD2 are responsible for approximately 15% of the autosomal dominant polycystic kidney disease cases. This gene encodes polycystin-2, a calcium-permeable cation channel whose C-terminal intracytosolic tail (PC2t) plays an important role in its interaction with a number of different proteins. In the present study, we have comprehensively evaluated the macromolecular assembly of PC2t homooligomer using a series of biophysical and biochemical analyses. Our studies, based on a new delimitation of PC2t, have revealed that it is capable of assembling as a homotetramer independently of any other portion of the molecule. Our data support this tetrameric arrangement in the presence and absence of calcium. Molecular dynamics simulations performed with a modified all-atoms structure-based model supported the PC2t tetrameric assembly, as well as how different populations are disposed in solution. The simulations demonstrated, indeed, that the best-scored structures are the ones compatible with a fourfold oligomeric state. These findings clarify the structural properties of PC2t domain and strongly support a homotetramer assembly of PC2.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1106766108