A proposed signaling motif for nuclear import in mRNA processing via the formation of arginine claw

doi:10.1073/pnas.0703151104

A proposed signaling motif for nuclear import in mRNA processing via the formation of arginine claw

Howard Hughes Medical Institute, Center for Theoretical Biological Physics, Department of Chemistry and Biochemistry, Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093-0365

Edited by Robert M. Stroud, University of California, San Francisco, CA, and approved July 26, 2007 (received for review April 5, 2007)

Abstract

Phosphorylation of proteins by kinases is the most commonly studied class of posttranslational modification, yet its structural consequences are not well understood. The human SR (serine-arginine) protein ASF/SF2 relies on the processive phosphorylation of the serine residues of eight consecutive arginine-serine (RS) dipeptide repeats at the C terminus by SRPK1 before it can be transported into the nucleus. This SR protein plays critical roles in spliceosome assembly, pre-mRNA splicing, and mRNA export, and the phosphorylation process of the RS repeats has been extensively studied experimentally. However, knowledge of the conformational changes associated with the phosphorylation of this simple sequence and how it triggers the importation of the SR protein is lacking. Here, we have carried out extensive molecular dynamics simulations to show that phosphorylation of the eight RS repeats significantly alters the peptide's conformation and leads to the formation of very stable structures that are likely to be involved in the recognition, binding, and transport of the SR protein. Specifically, we found an unusual symmetry-broken phase of conformations of the repetitive and quasi-symmetric phosphorylated peptide sequence. One of the main characteristics of these conformations is the exposed phosphate groups on the periphery, which possibly could serve as the recognition platform for the transport protein transportin-SR2.

Footnotes

*To whom correspondence may be addressed at:
Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, MC 0365, La Jolla, CA 92093-0365.
E-mail: dhamelbe{at}mccammon.ucsd.edu
Author contributions: D.H., T.S., and J.A.M. designed research; D.H. performed research; D.H. and T.S. analyzed data; and D.H., T.S., and J.A.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Abbreviations:

RS,

arginine-serine;

SR,

serine-arginine;

NLS,

nuclear localization signal;

TRN,

transportin;

GB,

generalized Born.
Freely available online through the PNAS open access option.