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Targeting the Calcineurin-NFAT Inter...

Li, Shuai.

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Targeting the Calcineurin-NFAT Interaction by Solution NMR Spectroscopy.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Targeting the Calcineurin-NFAT Interaction by Solution NMR Spectroscopy./
作者:	Li, Shuai.
面頁冊數:	126 p.
附註:	Source: Dissertation Abstracts International, Volume: 76-09(E), Section: B.
Contained By:	Dissertation Abstracts International76-09B(E).
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3700506
ISBN:	9781321704983

Targeting the Calcineurin-NFAT Interaction by Solution NMR Spectroscopy.
Li, Shuai.

Targeting the Calcineurin-NFAT Interaction by Solution NMR Spectroscopy. - 126 p.

Source: Dissertation Abstracts International, Volume: 76-09(E), Section: B.

Thesis (Ph.D.)--Harvard University, 2015.

This item is not available from ProQuest Dissertations & Theses.

The serine/threonine phosphatase calcineurin (Cn) targets the nuclear factors of activated T cells (NFATs) that activate cytokine genes. Calcium influx activates Cn to dephosphorylate multiple serine residues within the ~200 residue NFAT regulatory domain, which triggers joint nuclear translocation of NFAT and Cn. The dephosphorylation process relies on the interaction between Cn and the conserved motifs PxIxIT and LxVP, which are located N- and C-terminal to the phosphorylation sites in NFAT's regulatory domain. Here, we show that an NFATc1-derived 15-residue peptide segment containing the conserved LxVP motif binds to an epitope on Cn's catalytic domain (CnA), which overlaps with the previously established PxIxIT binding site on CnA and is distant to the regulatory domain (CnB). Both NFAT motifs partially compete for binding but do not fully displace each other on the CnA epitope, revealing that both segments bind simultaneously to the same epitope on the catalytic domain.

ISBN: 9781321704983Subjects--Topical Terms:

518028
Biochemistry.

Targeting the Calcineurin-NFAT Interaction by Solution NMR Spectroscopy.
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245 1 0 $a Targeting the Calcineurin-NFAT Interaction by Solution NMR Spectroscopy.
300 $a 126 p.
500 $a Source: Dissertation Abstracts International, Volume: 76-09(E), Section: B.
500 $a Adviser: Gerhard Wagner.
502 $a Thesis (Ph.D.)--Harvard University, 2015.
506 $a This item is not available from ProQuest Dissertations & Theses.
520 $a The serine/threonine phosphatase calcineurin (Cn) targets the nuclear factors of activated T cells (NFATs) that activate cytokine genes. Calcium influx activates Cn to dephosphorylate multiple serine residues within the ~200 residue NFAT regulatory domain, which triggers joint nuclear translocation of NFAT and Cn. The dephosphorylation process relies on the interaction between Cn and the conserved motifs PxIxIT and LxVP, which are located N- and C-terminal to the phosphorylation sites in NFAT's regulatory domain. Here, we show that an NFATc1-derived 15-residue peptide segment containing the conserved LxVP motif binds to an epitope on Cn's catalytic domain (CnA), which overlaps with the previously established PxIxIT binding site on CnA and is distant to the regulatory domain (CnB). Both NFAT motifs partially compete for binding but do not fully displace each other on the CnA epitope, revealing that both segments bind simultaneously to the same epitope on the catalytic domain.
520 $a The Cn-NFAT signaling pathway has been well credentialed as a potential target in the treatment of graft transplant rejection, autoimmune diseases and cardiovascular disorders, and is a common target of immunosuppressive drugs cyclosporin A (CsA) and FK506. Although effective in the disruption of Cn phosphatase activity, CsA and FK506 also result in undesired side effects and toxicity, promoting the discovery of alternative inhibitors which can selectively inhibit the Cn-NFAT interaction without altering the functioning of other Cn substrates. Several peptides directly inhibiting NFAT binding to Cn, as well as several small molecule inhibitors of NFAT-Cn association targeting an allosteric site on Cn have been developed previously. However, to-date there have been no reported small molecule inhibitors directed against the PxIxIT-binding site on Cn. Here, we report the fragment-based discovery of several direct-acting small molecule inhibitors targeting the Cn-NFAT interaction, and show that they selectively inhibit NFAT-dephosphorylation and NFAT-mediated gene expression without affecting Cn phosphatase activity against other substrates. We further demonstrate that the binding site for these inhibitors coincides with the core PxIxIT-binding site on Cn. The development of these inhibitors provides a new tool for probing Cn-NFAT signaling, further optimization of which may provide an alternative strategy for immunosuppressive therapy.
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650 4 $a Analytical chemistry. $3 3168300
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710 2 $a Harvard University. $b Chemistry and Chemical Biology. $3 2094763
773 0 $t Dissertation Abstracts International $g 76-09B(E).
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