Engineering peptide inhibitors to overcome PDZ binding promiscuity.
Engineering peptide inhibitors to overcome PDZ binding promiscuity.
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DOI：
10.1002/anie.201005575
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发表时间：
2010-12-17
影响因子：
16.6
通讯作者：
Boisguerin, Prisca
中科院分区：
文献类型：
--
作者：
Vouilleme, Lars;Cushing, Patrick R.;Volkmer, Rudolf;Madden, Dean R.;Boisguerin, Prisca
Protein–protein interaction domains (PPIDs) are key elements in assembling functional protein complexes and controlling cellular activities. A major class of PPIDs is mediated by PDZ (for PSD-95, Dlg, ZO-1) domains,[1–3] widespread scaffolding modules essential for the localization and activity of numerous cellular effector proteins. Among the diverse protein interaction domains, PDZ domains are highly conserved in organisms from bacteria to humans.[4] They usually bind the C-terminus of their ligands. Consistent with their structural homology, PDZ domains exhibit overlapping recognition sequences, meaning that a given partner typically can interact with multiple domains. Some years ago, we proposed a general and efficient procedure for profiling PDZ–peptide interactions that provides a picture of specificity and selectivity covering the complete PDZ–ligand sequence space by combining SPOT synthesis and Kd prediction.[5] As expected, among the three PDZ domains that were analyzed (AF6, ERBIN, and SNA1), the overlap of ligand sequences recognized at Kd values between 50–100 μm was substantial. Recent studies have suggested that there is more diversity among PDZ sequence preferences than originally thought.[6, 7] Nevertheless, the set of PDZ domains interacting with a given protein necessarily shares overlapping binding motifs, and it remains challenging to develop a canonical peptide that will inhibit only a single PDZ domain out of this set.To address this issue, we focused on a set of five PDZ domains known to interact with the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). The PDZ-containing proteins CAL (CFTR-associated ligand)[8, 9] and its antagonists NHERF1 and NHERF2 (Na+/H+ exchanger regulatory factors 1 and 2),[8, 10] compete for binding to CFTR. CAL contains one (CALP) and each NHERF protein two PDZ domains (N1P1, N1P2, N2P1 and N2P2) which control both the activity and the cell surface abundance of CFTR. NHERF family members increase CFTR activity at the apical membrane, whereas CAL promotes its lysosomal degradation. Thus, to explore novel therapeutic strategies for increasing the cell-surface abundance of CFTR, our goal was to design a selective inhibitor of the CFTR–CAL interaction that does not affect the biologically relevant PDZ competitors NHERF1 and NHERF2.[8]
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影响因子：
16.6
作者：
Cushing, Patrick R.;Vouilleme, Lars;Madden, Dean R.
通讯作者：
Madden, Dean R.
影响因子：
64.8
作者：
Grigoryan, Gevorg;Reinke, Aaron W.;Keating, Amy E.
通讯作者：
Keating, Amy E.
影响因子：
2.2
作者：
Frank, R
通讯作者：
Frank, R
影响因子：
56.9
作者：
Songyang, Z;Fanning, AS;Cantley, LC
通讯作者：
Cantley, LC
DOI：
10.1016/j.bbrc.2006.06.112
发表时间：
2006-08-25
影响因子：
3.1
作者：
Favia, M.;Fanelli, T.;Casavola, V.
通讯作者：
Casavola, V.