Association of the Cystic Fibrosis Transmembrane Regulator with CAL: Structural Features and Molecular Dynamics

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• 作者：Andrea Piserchio ; Abigail Fellows ; Dean R. Madden ; and Dale F. Mierke
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：December 13, 2005
• 年：2005
• 卷：44
• 期：49
• 页码：16158 - 16166
• 全文大小：613K
• 年卷期：v.44,no.49(December 13, 2005)
• ISSN：1520-4995

文摘

The association of the cystic fibrosis transmembrane regulator (CFTR) with two PDZ-containingmolecular scaffolds (CAL and EBP50) plays an important role in CFTR trafficking and membranemaintenance. The CFTR-molecular scaffold interaction is mediated by the association of the C-terminusof the transmembrane regulator with the PDZ domains. Here, we characterize the structure and dynamicsof the PDZ of CAL and the complex formed with CFTR employing high-resolution NMR. On the basisof NMR relaxation data, the rs/alpha.gif" BORDER=0>2 helix as well as the rs/beta2.gif" BORDER=0 ALIGN="middle">2-rs/beta2.gif" BORDER=0 ALIGN="middle">3 loop of CAL PDZ domain undergoes rapiddynamics. Molecular dynamics simulations suggest a concerted motion between the rs/alpha.gif" BORDER=0>2 helix and thers/beta2.gif" BORDER=0 ALIGN="middle">1-rs/beta2.gif" BORDER=0 ALIGN="middle">2 and rs/beta2.gif" BORDER=0 ALIGN="middle">2-rs/beta2.gif" BORDER=0 ALIGN="middle">3 loops, elements which define the binding pocket, suggesting that dynamics may playa role in PDZ-ligand specificity. The C-terminus of CFTR binds to CAL with the final four residues(-D^-3-T-R-L⁰) within the canonical PDZ-binding motif, between the rs/beta2.gif" BORDER=0 ALIGN="middle">2 strand and the rs/alpha.gif" BORDER=0>2 helix. The R^-1and D^-3 side chains make a number of contacts with the PDZ domain; many of these interactions differfrom those in the CFTR-EBP50 complex, suggesting sites that can be targeted in the development ofPDZ-selective inhibitors that may help modulate CFTR function.