A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin

Siekierka, John; Hung, Shirley H.Y.; Poe, Martin; Lin, C. Shirley; Sigal, Nolan H.

doi:10.1038/341755a0

Cited by 952 publications

(502 citation statements)

References 18 publications

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“…FK506 (tacrolimus) was approved as an oral immunosuppressant drug to be used after allogeneic transplant in 1994. The direct target for FK506 is the peptidyl-prolyl isomerase FK506 binding protein (FKBP) [28]. Very similar to CsA, also the effective physiological target of FK506 is not FKBP alone but a complex of the FKBP-bound FK506 and the phosphatase calcineurin [24].…”

Section: Fk506 (Tacrolimus)mentioning

confidence: 99%

Stabilization of protein–protein interactions by small molecules

Giordanetto¹,

Schäfer

Ottmann

2014

Drug Discovery Today

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Section: Fk506 (Tacrolimus)mentioning

confidence: 99%

Stabilization of protein–protein interactions by small molecules

Giordanetto¹,

Schäfer

Ottmann

2014

Drug Discovery Today

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“…It is self-evident that all of the hepatotrophic and antihepatotrophic molecules listed in Table 1 can induce profound changes in the immune system, and that most of these molecules are primarily associated either with normal immune function or its therapeutic alteration: i.e., the three T-lymphocyte-directed immunosuppressants (cyclosporine, tacrolimus, rapamycin); three cytokines (HGF, TGF-␣, TGF-␤); and a ubiquitous immunophillin (FKBP12) to which tacrolimus binds and which in turn binds 84,85 to TGF-␤ family Type I receptors 86 with inhibition of TGF-␤ signalling pathways. 87 Thus, it would be premature to conclude that regeneration is not a complex immunologic event of very early evolutionary development as we have suggested previously, 30 or that ALR is not a combined immune-and growth-regulatory gene.…”

Section: Discussionmentioning

confidence: 99%

A fresh look at augmenter of liver regeneration in rats

et al. 1999

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Augmenter of liver regeneration (ALR) is a hepatotrophic protein originally identified by bioassay in regenerating rat and canine livers following partial hepatectomy and in the hyperplastic livers of weanling rats, but not in resting adult livers. The ALR gene and gene product were subsequently described, but little is known about the cellular/subcellular sites of ALR synthesis in the liver, or about the release and dissemination of the peptide. To obtain this information in rats, we raised antibodies in rabbits against rat ALR for development of an enzyme-linked immunosorbent assay (ELISA). ALR concentrations were then determined in intact livers of unaltered weanling and adult rats; in regenerating residual liver after partial hepatectomy; in cultured hepatocytes and nonparenchymal cells (NPCs); and in culture medium and serum. ALR in the various liver cells was localized with immunohistochemistry. In addition, hepatic ALR and ALR mRNA were assayed with Western blotting and reversetranscriptase polymerase chain reaction (RT-PCR), respectively. The hepatocyte was the predominant liver cell in which ALR was synthesized and stored; the cultured hepatocytes secreted ALR into the medium in a timedependent fashion. Contrary to previous belief, the ALR peptide and ALR mRNA were present in comparable concentrations in the hepatocytes of both weanling and resting adult livers, as well as in cultured hepatocytes. A further unexpected finding was that hepatic ALR levels decreased for 12 hours after 70% hepatectomy in adult rats and then rose with no corresponding change in mRNA transcripts. In the meantime, circulating (serum) ALR levels increased up to 12 hours and declined thereafter. Thus, ALR appears to be constitutively expressed in hepatocytes in an inactive form, and released from the cells in an active form by unknown means in response to partial hepatectomy and under other circumstances of liver maturation (as in weanling rats) or regeneration. (HEPATOLOGY 1999;29:1435-1445.)The control of hepatic growth and regeneration has interested experimentalists for much of the 20th century. 1 Soon after the classical description in 1931 by Higgins and Anderson 2 of liver regeneration in rats following 70% hepatectomy, a search began for growth factors within the liver itself. McJunkin and Breuhaus 3 observed that the modest mitotic response to a 30% to 40% hepatectomy in rats was enhanced with an intraperitoneal injection 2 days postoperatively of homogenized homologous rat liver. Two decades later, Teir and Ravanti 4 and Blomquist 5 noted that this ''augmentation'' effect was demonstrable only when the injected homogenates were prepared from regenerating liver fragments following hepatectomy or from weanling rat livers that have a naturally heightened mitotic index. Subsequently, LaBrecque and Pesch 6 reported the same prerequisite of a hyperplastic liver source for cytosol extracts containing a putative ''hepatic stimulatory substance'' (HSS).Importantly, however, a cocondition for demonstrating a mitosis-augmenting a...

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“…Similar to CyP, the FK506 binding protein (FKBP) is an active PPIase (Harding et al, 1989;Siekierka et al, 1989). Both the FKBP-FKSO6 and the CyPCsA complexes have been shown to inhibit the in vitro activity of protein phosphatase 2B, calcineurin (Friedman & Weissman, 1991;Liu et al, 1991b).…”

mentioning

confidence: 99%

Active site mutants of human cyclophilin A separate peptidyl‐prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition

et al. 1992

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Based on recent X-ray structural information, six site-directed mutants of human cyclophilin A (hCyPA) involving residues in the putative active site--54, R55, F60, Q l l l , F113, and H126-have been constructed, overexpressed, and purified from Escherichia coli to homogeneity. The proteins W121A (Liu, J., Chen, C.-M., & Walsh, C.T., 1991a, Biochemistry30, 2306-2310), H54Q, R55A, F60A, Q l l l A , F113A, and H126Q were assayed for cis-trans peptidyl-prolyl isomerase (PPIase) activity, their ability to bind the immunosuppressive drug cyclosporin A (CsA), and protein phosphatase 2B (calcineurin) inhibition in the presence of CsA. Results indicate that H54Q, Q l l l A , F113A, and W121A retain 3-15% of the catalytic efficiency (kcoJKm) of wild-type recombinant hCyPA. The remaining three mutants (R55A, F60A, and H126Q) each retain less than 1% of the wild-type catalytic efficiency, indicating participation by these residues in PPIase catalysis. Each of the mutants bound to a CsA affinity matrix. The mutants R55A, F60A, F113A, and H126Q inhibited calcineurin in the presence of CsA, whereas W121A did not. Although CsA is a competitive inhibitor of PPIase activity, it can complex with enzymatically inactive cyclophilins and inhibit the phosphatase activity of calcineurin.

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A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin

Cited by 952 publications

References 18 publications

Stabilization of protein–protein interactions by small molecules

Stabilization of protein–protein interactions by small molecules

A fresh look at augmenter of liver regeneration in rats

Active site mutants of human cyclophilin A separate peptidyl‐prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition

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