2kq6
From Proteopedia
The structure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca2+-dependent regulation of polycystin-2 channel activity
Structural highlights
Disease[PKD2_HUMAN] Defects in PKD2 are the cause of polycystic kidney disease 2 (PKD2) [MIM:613095]. PKD2 is a disorder characterized by progressive formation and enlargement of cysts in both kidneys, typically leading to end-stage renal disease in adult life. Cysts also occurs in the liver and other organs. It represents approximately 15% of the cases of autosomal dominant polycystic kidney disease. PKD2 is clinically milder than PKD1 but it has a deleterious impact on overall life expectancy.[1] [2] [3] [4] [5] [6] [7] [8] [9] Function[PKD2_HUMAN] Involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (By similarity). PKD1 and PKD2 may function through a common signaling pathway that is necessary for normal tubulogenesis (By similarity). Acts as a regulator of cilium length, together with PKD1 (By similarity). The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling. The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling (By similarity). Functions as a calcium permeable cation channel. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe C-terminal cytoplasmic tail of polycystin-2 (PC2/TRPP2), a Ca(2+)-permeable channel, is frequently mutated or truncated in autosomal dominant polycystic kidney disease. We have previously shown that this tail consists of three functional regions: an EF-hand domain (PC2-EF, 720-797), a flexible linker (798-827), and an oligomeric coiled coil domain (828-895). We found that PC2-EF binds Ca(2+) at a single site and undergoes Ca(2+)-dependent conformational changes, suggesting it is an essential element of Ca(2+)-sensitive regulation of PC2 activity. Here we describe the NMR structure and dynamics of Ca(2+)-bound PC2-EF. Human PC2-EF contains a divergent non-Ca(2+)-binding helix-loop-helix (HLH) motif packed against a canonical Ca(2+)-binding EF-hand motif. This HLH motif may have evolved from a canonical EF-hand found in invertebrate PC2 homologs. Temperature-dependent steady-state NOE experiments and NMR R(1) and R(2) relaxation rates correlate with increased molecular motion in the EF-hand, possibly due to exchange between apo and Ca(2+)-bound states, consistent with a role for PC2-EF as a Ca(2+)-sensitive regulator. Structure-based sequence conservation analysis reveals a conserved hydrophobic surface in the same region, which may mediate Ca(2+)-dependent protein interactions. We propose that Ca(2+)-sensing by PC2-EF is responsible for the cooperative nature of PC2 channel activation and inhibition. Based on our results, we present a mechanism of regulation of the Ca(2+) dependence of PC2 channel activity by PC2-EF. Structure of the EF-hand domain of polycystin-2 suggests a mechanism for Ca2+-dependent regulation of polycystin-2 channel activity.,Petri ET, Celic A, Kennedy SD, Ehrlich BE, Boggon TJ, Hodsdon ME Proc Natl Acad Sci U S A. 2010 May 18;107(20):9176-81. Epub 2010 May 3. PMID:20439752[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Boggon, T J | Celic, A | Ehrlich, B E | Hodsdon, M E | Kennedy, S D | Petri, E T | Calcium | Coiled coil | Disease mutation | Glycoprotein | Ion transport | Ionic channel | Membrane | Phosphoprotein | Polymorphism | Protein x | Transmembrane | Transport | Transport protein
