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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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Structures of FKBP domains free and complexed to FK506 and a Hsp90 peptide. In (A), the crystal structure of the free Fk1 (active PPIase domain) of FKBP51 is shown. The Fk1 domain fold is conserved in all FKBPs; In (B) the crystal structure of the tandem Fk1-Fk2 domains of FKBP52 is depicted; In (C), the crystal structure of the tandem Fk1-Fk2 domains of FKBP52 bound to FK506 is shown; In (D), the interaction of the C-terminal TPR domain of FKBP52 with a Hsp90 pentapeptide (shown in blue) is depicted.
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biomolecules-05-00974-f003: Structures of FKBP domains free and complexed to FK506 and a Hsp90 peptide. In (A), the crystal structure of the free Fk1 (active PPIase domain) of FKBP51 is shown. The Fk1 domain fold is conserved in all FKBPs; In (B) the crystal structure of the tandem Fk1-Fk2 domains of FKBP52 is depicted; In (C), the crystal structure of the tandem Fk1-Fk2 domains of FKBP52 bound to FK506 is shown; In (D), the interaction of the C-terminal TPR domain of FKBP52 with a Hsp90 pentapeptide (shown in blue) is depicted.

Mentions: Human FKBP51 and FKBP52 show 55% sequence identity and have a common domain structure consisting of an N-terminal FKBP domain (Fk1), and FKBP-like domain (Fk2), and a TPR domain at the C-terminus. Several X-ray crystal structures and solution NMR structures of FKBP domains are now available (Table 2). All FKBP domains consist of a curved five-stranded antiparallel β-sheet that wraps around a short α-helix (Figure 3A). This core structure binds the substrate proline and is preserved in all structures. An additional α-helix is present in the Fk1 domain of FKBP51 (PDB code 3O5I) [48], but this region is disordered in the crystal structure of FKBP52 (PDB code 1Q1C, Figure 3B) [49]. The PPIase activity is limited to the Fk1 domain and no PPIase activity is observed for the Fk2 domain of FKBP52 [49]. Structural differences between the different FKBP proteins are localized to peripheral regions outside the core FK1 domain. The inhibitor FK506 is bound in a hydrophobic pocket near the central α-helix. The FK506 ligand is involved in an extensive network of hydrogen bonding interactions with the Fk1 domain as well as aromatic stacking interactions with Trp, Tyr, and Phe residues (Figure 3C). The crystal structure of the C-terminal TPR domain of FKBP52 (PDB code 1QZ2) bound to an Hsp90 peptide illustrates how accessory domains participate in mediating protein-protein interactions (Figure 3D).


Roles of Prolyl Isomerases in RNA-Mediated Gene Expression.

Thapar R - Biomolecules (2015)

Structures of FKBP domains free and complexed to FK506 and a Hsp90 peptide. In (A), the crystal structure of the free Fk1 (active PPIase domain) of FKBP51 is shown. The Fk1 domain fold is conserved in all FKBPs; In (B) the crystal structure of the tandem Fk1-Fk2 domains of FKBP52 is depicted; In (C), the crystal structure of the tandem Fk1-Fk2 domains of FKBP52 bound to FK506 is shown; In (D), the interaction of the C-terminal TPR domain of FKBP52 with a Hsp90 pentapeptide (shown in blue) is depicted.
© Copyright Policy
Related In: Results  -  Collection

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

biomolecules-05-00974-f003: Structures of FKBP domains free and complexed to FK506 and a Hsp90 peptide. In (A), the crystal structure of the free Fk1 (active PPIase domain) of FKBP51 is shown. The Fk1 domain fold is conserved in all FKBPs; In (B) the crystal structure of the tandem Fk1-Fk2 domains of FKBP52 is depicted; In (C), the crystal structure of the tandem Fk1-Fk2 domains of FKBP52 bound to FK506 is shown; In (D), the interaction of the C-terminal TPR domain of FKBP52 with a Hsp90 pentapeptide (shown in blue) is depicted.
Mentions: Human FKBP51 and FKBP52 show 55% sequence identity and have a common domain structure consisting of an N-terminal FKBP domain (Fk1), and FKBP-like domain (Fk2), and a TPR domain at the C-terminus. Several X-ray crystal structures and solution NMR structures of FKBP domains are now available (Table 2). All FKBP domains consist of a curved five-stranded antiparallel β-sheet that wraps around a short α-helix (Figure 3A). This core structure binds the substrate proline and is preserved in all structures. An additional α-helix is present in the Fk1 domain of FKBP51 (PDB code 3O5I) [48], but this region is disordered in the crystal structure of FKBP52 (PDB code 1Q1C, Figure 3B) [49]. The PPIase activity is limited to the Fk1 domain and no PPIase activity is observed for the Fk2 domain of FKBP52 [49]. Structural differences between the different FKBP proteins are localized to peripheral regions outside the core FK1 domain. The inhibitor FK506 is bound in a hydrophobic pocket near the central α-helix. The FK506 ligand is involved in an extensive network of hydrogen bonding interactions with the Fk1 domain as well as aromatic stacking interactions with Trp, Tyr, and Phe residues (Figure 3C). The crystal structure of the C-terminal TPR domain of FKBP52 (PDB code 1QZ2) bound to an Hsp90 peptide illustrates how accessory domains participate in mediating protein-protein interactions (Figure 3D).

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