HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shen, T. Articles by Wolynes, P. G. Search for Related Content PubMed PubMed Citation Articles by Shen, T. Articles by Wolynes, P. G.

The folding energy landscape and phosphorylation: modeling the conformational switch of the NFAT regulatory domain

Tongye Shen^*,, Chenghang Zong^*,, Donald Hamelberg^,, J. Andrew McCammon^*,, and Peter G. Wolynes^*,,1

^* Department of Chemistry and Biochemistry
Center for Theoretical Biological Physics, La Jolla, California, USA; and
Howard Hughes Medical Institute and Department of Pharmacology, University of California, San Diego

¹Correspondence: 9500 Gilman Dr., Mail Code 0371, La Jolla, CA 92093-0371, USA. E-mail: pwolynes{at}chem.ucsd.edu

An energy landscape approach predicts the conformational changes of the configurations of the regulatory domain of the protein nuclear factor of activated T cells (NFAT) caused by phosphorylation of specific multiple sites. Structurally local effects and secondary structural changes are modeled using all-atom Brownian dynamics to investigate the changes of the backbone torsional distributions upon phosphorylation. For tertiary and global changes, we employ a coarse-grained model to sample ensembles of conformations both with and without phosphorylation. At the secondary structure level, phosphorylation moderately increases the helical propensity and gives a more rigid local backbone conformation. The tertiary effects of phosphorylation caused by the extensive charge modification are more pronounced and collectively change the conformation of the regulatory domain of NFAT from a flexible globular ensemble to a rather rigid helical bundle, blocking access to the nuclear localization sequence. These studies give computational support to one scenario conjectured from experiments.— Shen, T., Zong, C., Hamelberg, D., McCammon, J. A., Wolynes, P. G. The folding energy landscape and phosphorylation: modeling the conformational switch of the NFAT regulatory domain.

Key Words: conformational switch • transcription factor • effective charge • multi-phosphorylation • contact-map PCA

This article has been cited by other articles:

				M. O. Collins, L. Yu, I. Campuzano, S. G. N. Grant, and J. S. Choudhary Phosphoproteomic Analysis of the Mouse Brain Cytosol Reveals a Predominance of Protein Phosphorylation in Regions of Intrinsic Sequence Disorder Mol. Cell. Proteomics, July 1, 2008; 7(7): 1331 - 1348. [Abstract] [Full Text] [PDF]

				D. Shental-Bechor and Y. Levy Effect of glycosylation on protein folding: A close look at thermodynamic stabilization PNAS, June 17, 2008; 105(24): 8256 - 8261. [Abstract] [Full Text] [PDF]

				D. Hamelberg, T. Shen, and J. A. McCammon A proposed signaling motif for nuclear import in mRNA processing via the formation of arginine claw PNAS, September 18, 2007; 104(38): 14947 - 14951. [Abstract] [Full Text] [PDF]

				T. Lu, T. Shen, C. Zong, J. Hasty, and P. G. Wolynes Statistics of cellular signal transduction as a race to the nucleus by multiple random walkers in compartment/phosphorylation space PNAS, November 7, 2006; 103(45): 16752 - 16757. [Abstract] [Full Text] [PDF]