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Roles of Prolyl Isomerases in RNA-Mediated Gene Expression.

Thapar R - Biomolecules (2015)

Bottom Line: The immunosuppressive drugs act by a gain-of-function mechanism by promoting protein-protein interactions in vivo.Several immunophilins have been identified as components of the spliceosome and are essential for alternative splicing.The functions of ribonucleoprotein associated PPIases are largely unknown.

View Article: PubMed Central - PubMed

Affiliation: BioSciences at Rice-Biochemistry and Cell Biology, Rice University, Houston, TX 77251-1892, USA. rthapar@rice.edu.

ABSTRACT
The peptidyl-prolyl cis-trans isomerases (PPIases) that include immunophilins (cyclophilins and FKBPs) and parvulins (Pin1, Par14, Par17) participate in cell signaling, transcription, pre-mRNA processing and mRNA decay. The human genome encodes 19 cyclophilins, 18 FKBPs and three parvulins. Immunophilins are receptors for the immunosuppressive drugs cyclosporin A, FK506, and rapamycin that are used in organ transplantation. Pin1 has also been targeted in the treatment of Alzheimer's disease, asthma, and a number of cancers. While these PPIases are characterized as molecular chaperones, they also act in a nonchaperone manner to promote protein-protein interactions using surfaces outside their active sites. The immunosuppressive drugs act by a gain-of-function mechanism by promoting protein-protein interactions in vivo. Several immunophilins have been identified as components of the spliceosome and are essential for alternative splicing. Pin1 plays roles in transcription and RNA processing by catalyzing conformational changes in the RNA Pol II C-terminal domain. Pin1 also binds several RNA binding proteins such as AUF1, KSRP, HuR, and SLBP that regulate mRNA decay by remodeling mRNP complexes. The functions of ribonucleoprotein associated PPIases are largely unknown. This review highlights PPIases that play roles in RNA-mediated gene expression, providing insight into their structures, functions and mechanisms of action in mRNP remodeling in vivo.

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Related in: MedlinePlus

NMR and X-ray crystal structures of Pin1 free and bound to peptides are shown. In (A), the solution NMR structure (PDB code 1NMV) is depicted showing the Pin1 PPIase domain and the WW domain separated by a linker; In (B) two crystal structures of Pin1 bound to phosphopeptides are shown. In the first structure (PDB code 1F8A), the peptide interacts with the WW domain and in the second complex (PDB code 2ITK), the peptide interacts with the PPIase domain; In (C), the interactions of the WW domain with a doubly phosphorylated Ser-Pro peptide is shown. The phosphoserines are shown in blue and the arginine side chains from the WW domain are shown in red.
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biomolecules-05-00974-f004: NMR and X-ray crystal structures of Pin1 free and bound to peptides are shown. In (A), the solution NMR structure (PDB code 1NMV) is depicted showing the Pin1 PPIase domain and the WW domain separated by a linker; In (B) two crystal structures of Pin1 bound to phosphopeptides are shown. In the first structure (PDB code 1F8A), the peptide interacts with the WW domain and in the second complex (PDB code 2ITK), the peptide interacts with the PPIase domain; In (C), the interactions of the WW domain with a doubly phosphorylated Ser-Pro peptide is shown. The phosphoserines are shown in blue and the arginine side chains from the WW domain are shown in red.

Mentions: Numerous X-ray and NMR structures of full-length Pin1 and its sub-domains have been deposited in the Protein Data Bank (Table 3), either free or bound to peptide ligands and inhibitors. Pin1 has a two-domain structure consisting of an N-terminal WW domain and a C-terminal PPIase domain (Figure 4) [99,100]. Solution NMR studies show that the WW and PPIase domains rotate independently with different correlation times (Figure 4A) [101,102]. This is in contrast to crystal structures of Pin1 solved in the presence of peptide ligands where the phosphopeptide binds either the WW domain or the PPIase domain, but the two domains pack against each other to adopt a compact structure (Figure 4B) [100]. The mechanism by which Pin1 interacts with phosphoproteins to catalyze cis-trans prolyl isomerization therefore is not clear. Pin1 is capable of a bivalent interaction with its substrates [103] in which both the WW domain and the PPIase domain can interact independently with the substrate, suggesting it may be capable of interacting with two phosphoproteins or two phosphorylated S/T-P sites in the protein at the same time. The preferred substrate sequence for Pin1 is X-P-X-pS/T-P.


Roles of Prolyl Isomerases in RNA-Mediated Gene Expression.

Thapar R - Biomolecules (2015)

NMR and X-ray crystal structures of Pin1 free and bound to peptides are shown. In (A), the solution NMR structure (PDB code 1NMV) is depicted showing the Pin1 PPIase domain and the WW domain separated by a linker; In (B) two crystal structures of Pin1 bound to phosphopeptides are shown. In the first structure (PDB code 1F8A), the peptide interacts with the WW domain and in the second complex (PDB code 2ITK), the peptide interacts with the PPIase domain; In (C), the interactions of the WW domain with a doubly phosphorylated Ser-Pro peptide is shown. The phosphoserines are shown in blue and the arginine side chains from the WW domain are shown in red.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496705&req=5

biomolecules-05-00974-f004: NMR and X-ray crystal structures of Pin1 free and bound to peptides are shown. In (A), the solution NMR structure (PDB code 1NMV) is depicted showing the Pin1 PPIase domain and the WW domain separated by a linker; In (B) two crystal structures of Pin1 bound to phosphopeptides are shown. In the first structure (PDB code 1F8A), the peptide interacts with the WW domain and in the second complex (PDB code 2ITK), the peptide interacts with the PPIase domain; In (C), the interactions of the WW domain with a doubly phosphorylated Ser-Pro peptide is shown. The phosphoserines are shown in blue and the arginine side chains from the WW domain are shown in red.
Mentions: Numerous X-ray and NMR structures of full-length Pin1 and its sub-domains have been deposited in the Protein Data Bank (Table 3), either free or bound to peptide ligands and inhibitors. Pin1 has a two-domain structure consisting of an N-terminal WW domain and a C-terminal PPIase domain (Figure 4) [99,100]. Solution NMR studies show that the WW and PPIase domains rotate independently with different correlation times (Figure 4A) [101,102]. This is in contrast to crystal structures of Pin1 solved in the presence of peptide ligands where the phosphopeptide binds either the WW domain or the PPIase domain, but the two domains pack against each other to adopt a compact structure (Figure 4B) [100]. The mechanism by which Pin1 interacts with phosphoproteins to catalyze cis-trans prolyl isomerization therefore is not clear. Pin1 is capable of a bivalent interaction with its substrates [103] in which both the WW domain and the PPIase domain can interact independently with the substrate, suggesting it may be capable of interacting with two phosphoproteins or two phosphorylated S/T-P sites in the protein at the same time. The preferred substrate sequence for Pin1 is X-P-X-pS/T-P.

Bottom Line: The immunosuppressive drugs act by a gain-of-function mechanism by promoting protein-protein interactions in vivo.Several immunophilins have been identified as components of the spliceosome and are essential for alternative splicing.The functions of ribonucleoprotein associated PPIases are largely unknown.

View Article: PubMed Central - PubMed

Affiliation: BioSciences at Rice-Biochemistry and Cell Biology, Rice University, Houston, TX 77251-1892, USA. rthapar@rice.edu.

ABSTRACT
The peptidyl-prolyl cis-trans isomerases (PPIases) that include immunophilins (cyclophilins and FKBPs) and parvulins (Pin1, Par14, Par17) participate in cell signaling, transcription, pre-mRNA processing and mRNA decay. The human genome encodes 19 cyclophilins, 18 FKBPs and three parvulins. Immunophilins are receptors for the immunosuppressive drugs cyclosporin A, FK506, and rapamycin that are used in organ transplantation. Pin1 has also been targeted in the treatment of Alzheimer's disease, asthma, and a number of cancers. While these PPIases are characterized as molecular chaperones, they also act in a nonchaperone manner to promote protein-protein interactions using surfaces outside their active sites. The immunosuppressive drugs act by a gain-of-function mechanism by promoting protein-protein interactions in vivo. Several immunophilins have been identified as components of the spliceosome and are essential for alternative splicing. Pin1 plays roles in transcription and RNA processing by catalyzing conformational changes in the RNA Pol II C-terminal domain. Pin1 also binds several RNA binding proteins such as AUF1, KSRP, HuR, and SLBP that regulate mRNA decay by remodeling mRNP complexes. The functions of ribonucleoprotein associated PPIases are largely unknown. This review highlights PPIases that play roles in RNA-mediated gene expression, providing insight into their structures, functions and mechanisms of action in mRNP remodeling in vivo.

Show MeSH
Related in: MedlinePlus