NHERF-2 (2nd PDZ domain)
NHERF-2 (2nd PDZ domain): Human solute carrier family 9 isoform 3 regulator 2 - 2nd PDZ domain
PDB Code: 2HE4
PDZ domains function as protein-protein interaction modules. The best characterised interaction of the PDZ domain is with the C-terminal 4-5 residues of the target protein that binds in an extended fashion between the betaB strand and the alphaB helix of the PDZ domain. In many cases the protein that contains the PDZ domain contains additional PDZ domains or interaction modules. NHERF-2 is one such protein that contains two PDZ domains within its sequence.
The presence of multiple domains that can form various interactions allows these proteins to act as key components in a macromolecular assembly. Sun et al (2000) showed that the second PDZ domain of NHERF-2 interacts with the C-terminus of the CFTR but also NHERF-2 binds erzin, a linker protein between the plasma membrane and the actin cytoskeleton. As erzin is known to bind protein kinase A (PKA) it was suggested that through this assembly PKA can regulate CFTR via phosphorylation of the CFTR regulatory domain.
Another potential kinase/channel/PDZ interaction occurs between the vanilloid receptor TRPV5 whose C-terminus binds the second PDZ domain of NHERF-2 and the serum and glucocorticoid inducible kinase SGK 1 which activates TRPV5. As TRPV5 functions as a calcium channel in this instance NHERF-2 plays a role within cellular calcium homeostasis.
Other membrane proteins that bind to the second PDZ domain of NHERF-2 include the ATP gated channel P2Y1, the sulphate transporter SLC 26A3 mutations in this gene have been associated with congenital chloride diarrhea and the endothelial differentiation, lysophosphatidic acid G-protein-coupled receptor 4 LPA2 which is upregulated in several forms of cancer.
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