FK506 binding protein 51: Its role in the adipose organ and beyond

Galigniana, Natalia M.; Ruiz, Marina C; Piwien-Pilipuk, Graciela

doi:10.1002/jcb.30351

J of Cellular Biochemistry

2022

DOI: 10.1002/jcb.30351

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FK506 binding protein 51: Its role in the adipose organ and beyond

Natalia M. Galigniana

Marina C Ruiz

Graciela Piwien-Pilipuk

Abstract: There is a great body of evidence that the adipose organ plays a central role in the control not only of energy balance, but importantly, in the maintenance of metabolic homeostasis. Interest in the study of different aspects of its physiology grew in the last decades due to the pandemic of obesity and the consequences of metabolic syndrome. It was not until recently that the first evidence for the role of the high molecular weight immunophilin FK506 binding protein (FKBP) 51 in the process of adipocyte differ… Show more

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2023

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Cited by 3 publications

References 160 publications

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Entdeckung eines potenten PROTAC ermöglicht die gezielte Ausschaltung der Gerüstfunktionen von FKBP51

Geiger,

Walz,

Meyners

et al. 2023

Angewandte Chemie

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Das FK506‐bindende Protein 51 (FKBP51) stellt ein vielversprechendes Wirkstoffziel zur Behandlung von verschiedenen Krankheiten dar, darunter Depression, chronischer Schmerz und Fettleibigkeit. Bisherige FKBP51‐gerichtete Wirkstoffe waren auf die Blockade der FK506‐Bindestelle beschränkt, wodurch Kernfunktionen von FKBP51 jedoch nicht beeinträchtigt werden. Hier präsentieren wir die Entwicklung des ersten FKBP51 Proteolysis Targeting Chimeras (PROTAC), der den Abbau von FKBP51 ermöglicht und damit auch die Gerüstfunktion von FKBP51 ausschalten kann. Die initiale Synthese von 220 FKBP‐gerichteten PROTACs ergab eine Vielzahl aktiver PROTACs für FKBP12, sechs für FKBP51 und keinen für FKBP52. Die Strukturanalyse eines binären FKBP12:PROTAC‐Komplexes offenbarte die molekulare Grundlage für negative Kooperativität. Die Linker‐Optimierung eines FKBP51 PROTACs der ersten Generation führte zur Entwicklung von SelDeg51 mit verbesserter zellulärer Aktivität, Selektivität und hoher Kooperativität. Die Struktur des ternären FKBP51:SelDeg51:VCB Komplexes zeigte, wie SelDeg51 durch Dimerisierung von FKBP51 und VHL Kooperativität herstellt, die dem Bindungsmodus von molekularen Klebern ähnelt. SelDeg51 baut FKBP51 auf effiziente Weise in Zellen ab und reaktiviert den GR‐Signalweg, was die erhöhte Wirksamkeit des Proteinabbaus im Vergleich zur klassischen FKBP51‐Besetzung demonstriert.

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Entdeckung eines potenten PROTAC ermöglicht die gezielte Ausschaltung der Gerüstfunktionen von FKBP51

Geiger,

Walz,

Meyners

et al. 2023

Angewandte Chemie

View full text Add to dashboard Cite

show abstract

Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

Geiger,

Walz,

Meyners

et al. 2023

Angew Chem Int Ed

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The FK506‐binding protein 51 (FKBP51) is a promising target in a variety of disorders including depression, chronic pain, and obesity. Previous FKBP51‐targeting strategies were restricted to occupation of the FK506‐binding site, which does not affect core functions of FKBP51. Here, we report the discovery of the first FKBP51 proteolysis targeting chimera (PROTAC) that enables degradation of FKBP51 abolishing its scaffolding function. Initial synthesis of 220 FKBP‐focused PROTACs yielded a plethora of active PROTACs for FKBP12, six for FKBP51, and none for FKBP52. Structural analysis of a binary FKBP12:PROTAC complex revealed the molecular basis for negative cooperativity. Linker‐based optimization of first generation FKBP51 PROTACs led to the PROTAC SelDeg51 with improved cellular activity, selectivity, and high cooperativity. The structure of the ternary FKBP51:SelDeg51:VCB complex revealed how SelDeg51 establishes cooperativity by dimerizing FKBP51 and the von Hippel‐Lindau protein (VHL) in a glue‐like fashion. SelDeg51 efficiently depletes FKBP51 and reactivates glucocorticoid receptor (GR)‐signalling, highlighting the enhanced efficacy of full protein degradation compared to classical FKBP51 binding.

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Mitochondrial–nuclear communication by FKBP51 shuttling

Zgajnar

Lagadari

Gallo

et al. 2023

J of Cellular Biochemistry

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The HSP90‐binding immunophilin FKBP51 is a soluble protein that shows high homology and structural similarity with FKBP52. Both immunophilins are functionally divergent and often show antagonistic actions. They were first described in steroid receptor complexes, their exchange in the complex being the earliest known event in steroid receptor activation upon ligand binding. In addition to steroid‐related events, several pleiotropic actions of FKBP51 have emerged during the last years, ranging from cell differentiation and apoptosis to metabolic and psychiatric disorders. On the other hand, mitochondria play vital cellular roles in maintaining energy homeostasis, responding to stress conditions, and affecting cell cycle regulation, calcium signaling, redox homeostasis, and so forth. This is achieved by proteins that are encoded in both the nuclear genome and mitochondrial genes. This implies active nuclear‐mitochondrial communication to maintain cell homeostasis. Such communication involves factors that regulate nuclear and mitochondrial gene expression affecting the synthesis and recruitment of mitochondrial and nonmitochondrial proteins, and/or changes in the functional state of the mitochondria itself, which enable mitochondria to recover from stress. FKBP51 has emerged as a serious candidate to participate in these regulatory roles since it has been unexpectedly found in mitochondria showing antiapoptotic effects. Such localization involves the tetratricopeptide repeats domains of the immunophilin and not its intrinsic enzymatic activity of peptidylprolyl‐isomerase. Importantly, FKBP51 abandons the mitochondria and accumulates in the nucleus upon cell differentiation or during the onset of stress. Nuclear FKBP51 enhances the enzymatic activity of telomerase. The mitochondrial‐nuclear trafficking is reversible, and certain situations such as viral infections promote the opposite trafficking, that is, FKBP51 abandons the nucleus and accumulates in mitochondria. In this article, we review the latest findings related to the mitochondrial‐nuclear communication mediated by FKBP51 and speculate about the possible implications of this phenomenon.

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FK506 binding protein 51: Its role in the adipose organ and beyond

Cited by 3 publications

References 160 publications

Entdeckung eines potenten PROTAC ermöglicht die gezielte Ausschaltung der Gerüstfunktionen von FKBP51

Entdeckung eines potenten PROTAC ermöglicht die gezielte Ausschaltung der Gerüstfunktionen von FKBP51

Discovery of a Potent Proteolysis Targeting Chimera Enables Targeting the Scaffolding Functions of FK506‐Binding Protein 51 (FKBP51)

Mitochondrial–nuclear communication by FKBP51 shuttling

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