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BMC Biochemistry (1)
Structure (London, England : 1993) (1)
Ohki, Shin-ya (3)
Eto, Masumi (2)
Aikawa, Sei-ichi (1)
Alam, AHM Khurshid (1)
Brautigan, David L. (1)
Dam, Hieu Chi (1)
Isozumi, Noriyoshi (1)
Iwaoka, Ryou (1)
Kirkbride, Jason A. (1)
Kitazawa, Toshio (1)
Matsuzawa, Fumiko (1)
Mori, Shunsuke (1)
Nishimura, Yumi (1)
Sekiyama, Yoshiharu (1)
Sugiyama, Ayumu (1)
Suzuki, Hitoshi (1)
Takeuchi, Makoto (1)
Tsukahara, Toshifumi (1)
Vu, Luyen Thi (1)
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Solution structure of the inhibitory phosphorylation domain of myosin phosphatase targeting subunit 1
NMR; protein structure; phosphorylation; helix; dynamics
Phosphorylation-induced conformational switching of CPI-17 produces a potent myosin phosphatase inhibitor
Kirkbride, Jason A.
Brautigan, David L.
Structure (London, England : 1993)
Phosphorylation of endogenous inhibitor proteins specific for type-1 Ser/Thr phosphatase (PP1) provides a mechanism for reciprocal coordination of kinase and phosphatase activities. Phosphorylation of Thr38 in the inhibitor protein CPI-17 transduces G-protein-mediated signaling into a > 1000-fold increase of inhibitory potency toward myosin phosphatase. We show here the solution NMR structure of phospho-T38-CPI-17 with r. m. s. d. of 0.36 ± 0.06 Å for the backbone secondary structure, which reveals how phosphorylation triggers a conformational change and exposes the PP1 inhibitory surface. This active conformation is stabilized by the formation of a hydrophobic core of intercalated side-chains, which is not formed in a phospho-mimetic D38 mutant form of CPI-17. Thus, the profound increase in potency of CPI-17 arises from phosphorylation, conformational change and hydrophobic stabilization of a rigid structure that poses the phosphorylated residue on the protein surface and restricts its hydrolysis by myosin phosphatase. Our results provide structural insights into transduction of kinase signals by PP1 inhibitor proteins.
Alternative splicing produces structural and functional changes in CUGBP2
Alam, AHM Khurshid
Vu, Luyen Thi
Dam, Hieu Chi
CELF/Bruno-like proteins play multiple roles, including the regulation of alternative splicing and translation. These RNA-binding proteins contain two RNA recognition motif (RRM) domains at the N-terminus and another RRM at the C-terminus. CUGBP2 is a member of this family of proteins that possesses several alternatively spliced exons.
The present study investigated the expression of exon 14, which is an alternatively spliced exon and encodes the first half of the third RRM of CUGBP2. The ratio of exon 14 skipping product (R3δ) to its inclusion was reduced in neuronal cells induced from P19 cells and in the brain. Although full length CUGBP2 and the CUGBP2 R3δ isoforms showed a similar effect on the inclusion of the smooth muscle (SM) exon of the ACTN1 gene, these isoforms showed an opposite effect on the skipping of exon 11 in the insulin receptor gene. In addition, examination of structural changes in these isoforms by molecular dynamics simulation and NMR spectrometry suggested that the third RRM of R3δ isoform was flexible and did not form an RRM structure.
Our results suggest that CUGBP2 regulates the splicing of ACTN1 and insulin receptor by different mechanisms. Alternative splicing of CUGBP2 exon 14 contributes to the regulation of the splicing of the insulin receptor. The present findings specifically show how alternative splicing events that result in three-dimensional structural changes in CUGBP2 can lead to changes in its biological activity.
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