Phosphorylation mechanism and structure of serine-arginine protein kinases
Open Access
- 14 December 2010
- journal article
- review article
- Published by Wiley in The FEBS Journal
- Vol. 278 (4), 587-597
- https://doi.org/10.1111/j.1742-4658.2010.07992.x
Abstract
The splicing of mRNA requires a group of essential factors known as SR proteins, which participate in the maturation of the spliceosome. These proteins contain one or two RNA recognition motifs and a C‐terminal domain rich in Arg‐Ser repeats (RS domain). SR proteins are phosphorylated at numerous serines in the RS domain by the SR‐specific protein kinase (SRPK) family of protein kinases. RS domain phosphorylation is necessary for entry of SR proteins into the nucleus, and may also play important roles in alternative splicing, mRNA export, and other processing events. Although SR proteins are polyphosphorylated in vivo, the mechanism underlying this complex reaction has only been recently elucidated. Human alternative splicing factor [serine/arginine‐rich splicing factor 1 (SRSF1)], a prototype for the SR protein family, is regiospecifically phosphorylated by SRPK1, a post‐translational modification that controls cytoplasmic–nuclear localization. SRPK1 binds SRSF1 with unusually high affinity, and rapidly modifies about 10–12 serines in the N‐terminal region of the RS domain (RS1), using a mechanism that incorporates sequential, C‐terminal to N‐terminal phosphorylation and several processive steps. SRPK1 employs a highly dynamic feeding mechanism for RS domain phosphorylation in which the N‐terminal portion of RS1 is initially bound to a docking groove in the large lobe of the kinase domain. Upon subsequent rounds of phosphorylation, this N‐terminal segment translocates into the active site, and a β‐strand in RNA recognition motif 2 unfolds and occupies the docking groove. These studies indicate that efficient regiospecific phosphorylation of SRSF1 is the result of a contoured binding cavity in SRPK1, a lengthy Arg‐Ser repetitive segment in the RS domain, and a highly directional processing mechanism.Keywords
This publication has 67 references indexed in Scilit:
- Mechanism of Dephosphorylation of the SR Protein ASF/SF2 by Protein Phosphatase 1Journal of Molecular Biology, 2010
- Allosteric Interactions Direct Binding and Phosphorylation of ASF/SF2 by SRPK1Biochemistry, 2009
- Regiospecific Phosphorylation Control of the SR Protein ASF/SF2 by SRPK1Journal of Molecular Biology, 2009
- Kinase Domain Insertions Define Distinct Roles of CLK Kinases in SR Protein PhosphorylationStructure, 2009
- Adaptable Molecular Interactions Guide Phosphorylation of the SR Protein ASF/SF2 by SRPK1Journal of Molecular Biology, 2008
- The splicing factor SC35 has an active role in transcriptional elongationNature Structural & Molecular Biology, 2008
- A Sliding Docking Interaction Is Essential for Sequential and Processive Phosphorylation of an SR Protein by SRPK1Molecular Cell, 2008
- Structural and functional analysis of RNA and TAP binding to SF2/ASFEMBO Reports, 2007
- Phosphotyrosine interactome of the ErbB‐receptor kinase familyMolecular Systems Biology, 2005
- A serine kinase regulates intracellular localization of splicing factors in the cell cycleNature, 1994