Characterization of an Exchange Reaction between Soluble FKBP-12 and the FKBP·Ryanodine Receptor Complex

Timerman, Anthony P.; Wiederrecht, Gregory; Marcy, Alice I.; Fleischer, Sidney

doi:10.1074/jbc.270.6.2451

Cited by 131 publications

(120 citation statements)

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“…Using a dorsal root ganglia (DRG) expression library and FKBP domain I as "bait" we found that FKBP52 interacts with Atox1, a metallochaperone that transfers copper to Menkes Disease Protein (MNK) and Wilson Disease Protein (WD) (20). Whereas previous studies have shown that immunophilins can effect calcium metabolism and regulate calcium channels (21,22), our present data show for the first time that FKBP52 is implicated in the copper efflux machinery in mammalian cells. Yeast Two-hybrid Screen-A P1 to P3 neonatal rat DRG cDNA expression library inserted into the DNA activation domain pB42AD vector was kindly provided by Dr. Moses Chao (The Skirball Institute, New York University).…”

mentioning

confidence: 48%

A Novel Role for the Immunophilin FKBP52 in Copper Transport

Sanokawa-Akakura

Dai

Akakura

et al. 2004

Journal of Biological Chemistry

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FK506-binding protein 52 (FKBP52) is an immunophilin that possesses peptidylprolyl cis/trans-isomerase(PPIase) activity and is a component of a subclass of steroid hormone receptor complexes. Several recent studies indicate that immunophilins can regulate neuronal survival and nerve regeneration although the molecular mechanisms are poorly understood. To investigate the function of FKBP52 in the nervous system, we employed a yeast two-hybrid strategy using the PPIase domain (domain I) as bait to screen a neonatal rat dorsal root ganglia cDNA expression library. We identified an interaction between FKBP52 domain I and Atox1, a copper-binding metallochaperone. Atox1 interacts with Menkes disease protein and Wilson disease protein (WD) and functions in copper efflux. The interaction between FKBP52 and Atox1 was observed in both glutathione S-transferase pull-down experiments and when proteins were ectopically expressed in human embryonic kidney (HEK) 293T cells and was sensitive to FK506. Interestingly, the FKBP52/Atox1 interaction was enhanced when HEK 293T cells were cultured in copper-supplemented medium and decreased in the presence of the copper chelator, bathocuproine disulfate, suggesting that the interaction is regulated in part by intracellular copper. Overexpression of FKBP52 increased rapid copper efflux in 64 Cu-loaded cells, as did the overexpression of WD transporter. Taken together, our present findings suggest that FKBP52 is a component of the copper efflux machinery, and in so, may also promote neuroprotection from copper toxicity. FKBP521 is a high molecular weight FK506-binding immunophilin first identified as a component of steroid hormone receptor heterocomplexes (1). Analysis of mRNA and protein levels has demonstrated that FKBP52 is widely expressed in mammalian tissues but particularly abundant in the nervous system (2, 3). Structurally, FKBP52 contains an N-terminal peptidylprolyl cis-trans-isomerase (PPIase) domain (domain I), a FKBP-like pseudo domain (domain II), three tetratricopeptide repeat (TPR) domains (domain III) that mediate proteinprotein interactions with HSP90, and a C-terminal domain calmodulin-binding site (domain IV) (4, 5).FKBP52 has been shown to play important roles in a diverse number of intracellular processes, but much research has focused on its involvement in steroid hormone regulation. FKBP52 regulates the maturation of steroid hormone receptor complexes through interactions between its TPR domain and HSP90 chaperones, which act as scaffolds for receptor assembly and are thought to enhance the affinity of estrogen receptor and the glucocorticoid receptor toward their ligands (1, 6). The PPIase domain of FKBP52 facilitates translocation of the activated steroid receptors to the nucleus by binding to cytoplasmic dynein (7). FKBP52 serves as a transcriptional regulator by repressing the activity of interferon regulatory factor-4 in immune cells (8) and heat-shock factor-1 in HeLa cells (9). FKBP52 has been implicated in the cardiotrophic effect of cardiotrophin-1 (10...

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confidence: 48%

A Novel Role for the Immunophilin FKBP52 in Copper Transport

Sanokawa-Akakura

Dai

Akakura

et al. 2004

Journal of Biological Chemistry

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“…FKBP12 and FKBP12.6 (also known as calstabin 1 and 2, respectively) physically interact with all three isoforms of RyR but have different expression levels and binding affinity in different tissues (Chelu et al 2004). FKBP12 copurifies with RyR1 (Jayaraman et al 1992;Brillantes et al 1994) and FKBP12.6 copurifies with RyR2 (Timerman et al 1995;Timerman et al 1996;Barg et al 1997;Jeyakumar et al 2001;Masumiya et al 2003). Although somewhat controversial, a component of the FKBP12 binding site appears to be located between amino acids 2458 and 2468 of RyR1 (Rabbit sequence, SwissProt accession #P11716).…”

Section: Calsequestrinmentioning

confidence: 99%

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Lanner¹,

Georgiou²,

Joshi³

et al. 2010

Cold Spring Harbor Perspectives in Biology

658

572

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Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca 2þ from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (.2MDa) and exist as three mammalian isoforms (RyR 1 -3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.

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“…Mammalian FKBPs are known to bind and modulate calcium release channels (31,44). Furthermore, FKBP12 has been shown to regulate murine MDR3 activity, but attempts to demonstrate interaction have been thus far unsuccessful (33).…”

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confidence: 99%

Immunophilin-like TWISTED DWARF1 Modulates Auxin Efflux Activities of Arabidopsis P-glycoproteins

Bouchard

Bailly

Blakeslee

et al. 2006

Journal of Biological Chemistry

182

236

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The immunophilin-like protein TWISTED DWARF1 (TWD1/FKBP42) has been shown to physically interact with the multidrug resistance/P-glycoprotein (PGP) ATP-binding cassette transporters PGP1 and PGP19 (MDR1). Overlapping phenotypes of pgp1/pgp19 and twd1 mutant plants suggested a positive regulatory role of TWD1 in PGP-mediated export of the plant hormone auxin, which controls plant development. Here, we provide evidence at the cellular and plant levels that TWD1 controls PGP-mediated auxin transport. twd1 and pgp1/pgp19 cells showed greatly reduced export of the native auxin indole-3-acetic acid (IAA). Constitutive overexpression of PGP1 and PGP19, but not TWD1, enhanced auxin export. Coexpression of TWD1 and PGP1 in yeast and mammalian cells verified the specificity of the regulatory effect. Employing an IAA-specific microelectrode demonstrated that IAA influx in the root elongation zone was perturbed and apically shifted in pgp1/pgp19 and twd1 roots. Mature roots of pgp1/pgp19 and twd1 plants revealed elevated levels of free IAA, which seemed to account for agravitropic root behavior. Our data suggest a novel mode of PGP regulation via FK506-binding protein-like immunophilins, implicating possible alternative strategies to overcome multidrug resistance.

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Characterization of an Exchange Reaction between Soluble FKBP-12 and the FKBP·Ryanodine Receptor Complex

Cited by 131 publications

References 30 publications

A Novel Role for the Immunophilin FKBP52 in Copper Transport

A Novel Role for the Immunophilin FKBP52 in Copper Transport

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Immunophilin-like TWISTED DWARF1 Modulates Auxin Efflux Activities of Arabidopsis P-glycoproteins

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