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ABSTRACT: The PHD fingers of the human MLL and Drosophila trx proteins have strong amino acid sequence conservation but their function is unknown. We have determined that these fingers mediate homodimerization and binding of MLL to Cyp33, a nuclear cyclophilin. These two proteins interact in vitro and in vivo in mammalian cells and colocalize at specific nuclear subdomains. Overexpression of the Cyp33 protein in leukemia cells results in altered expression of HOX genes that are targets for regulation by MLL. These alterations are suppressed by cyclosporine and are not observed in cell lines that express a mutant MLL protein without PHD fingers. These results suggest that binding of Cyp33 to MLL modulates its effects on the expression of target genes.
Molecular and Cellular Biology 06/2001; 21(10):3589-97. · 5.53 Impact Factor
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ABSTRACT: Peptidyl-prolyl cis-trans-isomerases (PPIases) are enzymes capable of isomerizing a Xaa-Pro peptide bond. Three families of PPIases are known: cyclophilins, FKBPs, and parvulins. The physiological functions of the PPIases are only poorly understood. Eucaryotic members of the parvulin family have recently been shown to be essential for regulation of mitosis. Here we describe the purification and characterization of Ssp1, an abundant parvulin homolog from Neurospora crassa, which is unique among the known eucaryotic parvulins in containing a polyglutamine stretch between the N-terminal WW domain and the C-terminal PPIase domain. Ssp1 is a site-specific PPIase with respect to the amino acid N-terminal to the proline residue. Peptides with glutamate, phosphoserine, or phosphothreonine in the -1-position proved to be the best substrates. Ssp1 is not only able to isomerize small peptides but is also active in protein folding, as shown with mouse dihydrofolate reductase. Using the substrate specificity of Ssp1, we could identify Glu81-Pro82 as a PPIase-sensitive site in folding of dihydrofolate reductase. These results demonstrate that Ssp1 is a potent mediator of protein folding and that parvulins can serve as tools to elucidate rate-limiting steps in protein folding reactions.
Journal of Biological Chemistry 12/1998; 273(48):31971-6. · 4.77 Impact Factor
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ABSTRACT: Cyclophilins (CyPs) define a family of proteins binding to the immunosuppressive drug cyclosporin A (CsA). They are evolutionary highly conserved proteins being present in both pro- and eukaryotes and in different subcellular locations. CyPs possess enzymatic activity, namely peptidyl-prolyl cis-trans isomerase (PPIase) activity and are involved in cellular protein folding and protein interactions. Here we describe a novel interaction of human T cell cyclophilin18 (hCyP18). Abundant cytosolic hCyP18 binds to the thiol-specific antioxidant protein Aop1 and stimulates its enzymatic activity. Aop1 belongs to a family of proteins thought to be involved in defense of oxidative stress. The interaction of both proteins seem to be specific, since other PPIases do not have any stimulatory effect on Aop1.
Journal of Molecular Biology 04/1998; 277(4):763-9. · 4.00 Impact Factor
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ABSTRACT: Cyclophilins (CyPs) are binding proteins for the immunosuppressive drug cyclosporin A (CsA). CyPs are evolutionarily highly conserved proteins present in both pro- and eukaryotes as well as in different subcellular locations. CyPs possess enzymatic activity, namely peptidyl-prolyl cis-trans isomerase (PPIase) activity; CyPs are involved in cellular protein folding and protein interactions. To date, only cyclosporins and proteins are known to interact with CyPs. Here we describe a novel nuclear cyclophilin (hCyP33) from human T cells with an additional RNA-binding domain. This combines for the first time RNA binding and protein folding in one protein.
FEBS Letters 01/1997; 398(2-3):201-5. · 3.54 Impact Factor
