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 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.

Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) INCT-INBEQMeDI

Brazilian agency Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[2006/03098-8]

LIMs of University of Sao Paulo School of Medicine (USP)

Clinical Core Center [National Institutes of Health (NIH)][P30 DK090868]

CNPq

National Science Foundation (NSF)[PHY-0822283]

National Science Foundation (NSF)[MCB-1051438]