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Sci Rep. 2015 Jun 8;5:11127. doi: 10.1038/srep11127.

Structural and Dynamic Features of F-recruitment Site Driven Substrate Phosphorylation by ERK2.

Author information

1
Department of Chemistry, The City College of New York, New York, NY 10031.
2
1] Division of Medicinal Chemistry, University of Texas, Austin, TX 78712 [2] Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, El-Minia 61519, Egypt.
3
Department of Chemistry, The College of Staten Island, Staten Island, NY 10314.
4
The New York Structural Biology Center, New York, NY 10027.
5
Division of Medicinal Chemistry, University of Texas, Austin, TX 78712.
6
1] Department of Chemistry, The City College of New York, New York, NY 10031 [2] Graduate Center of CUNY, New York, NY 10016.

Abstract

The F-recruitment site (FRS) of active ERK2 binds F-site (Phe-x-Phe-Pro) sequences found downstream of the Ser/Thr phospho-acceptor on cellular substrates. Here we apply NMR methods to analyze the interaction between active ERK2 (ppERK2), and a 13-residue F-site-bearing peptide substrate derived from its cellular target, the transcription factor Elk-1. Our results provide detailed insight into previously elusive structural and dynamic features of FRS/F-site interactions and FRS-driven substrate phosphorylation. We show that substrate F-site engagement significantly quenches slow dynamics involving the ppERK2 activation-loop and the FRS. We also demonstrate that the F-site phenylalanines make critical contacts with ppERK2, in contrast to the proline whose cis-trans isomerization has no significant effect on F-site recognition by the kinase FRS. Our results support a mechanism where phosphorylation of the disordered N-terminal phospho-acceptor is facilitated by its increased productive encounters with the ppERK2 active site due to docking of the proximal F-site at the kinase FRS.

PMID:
26054059
PMCID:
PMC4459106
DOI:
10.1038/srep11127
[Indexed for MEDLINE]
Free PMC Article

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