FKBP51 and FKBP52 in signaling and disease

Storer, Cheryl L.; Dickey, Chad A.; Galigniana, Mario D.; Rein, Theo; Cox, Marc B.

doi:10.1016/j.tem.2011.08.001

Cited by 224 publications

(244 citation statements)

References 98 publications

Supporting

Mentioning

240

Contrasting

Order By: Relevance

“…These mutations include missense, nonsense, and deletion mutations (8 -10). AIP is a co-chaperone with Hsp90 in the maturation of the aryl hydrocarbon receptor (11), similar to the co-chaperone function of the FKBP and TPR domain-containing immunophilins FKBP51/52 that act on steroid hormone receptors (12). Furthermore, AIPL1 itself was found to interact with Hsp90 and Hsp70 (13).…”

mentioning

confidence: 76%

Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

Majumder

Gopalakrishna

Cheguru

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Mutations in AIPL1, a chaperone of the lipidated visual effector phosphodiesterase-6, cause severe childhood blindness. Results: AIPL1 binds the farnesyl lipid moiety. The unique insert region of AIPL1 is critical for this interaction. Conclusion: The AIPL1-farnesyl interaction suggests its role in the interaction with phosphodiesterase-6 and normal function of AIPL1. Significance: This study describes a novel mechanism of AIPL1 in retina disease.

show abstract

mentioning

confidence: 76%

Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

Majumder

Gopalakrishna

Cheguru

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…FKBP51's PPIase activity has a role in microtubule stabilisation through Hsp90-mediated dephoshorylation of tau 139,140 . On the other hand, FKBP52 is ubiquitously expressed at high levels and has been associated with microtubule destabilisation and tubulin depolymerisation [140][141][142] . FKBP51/FKBP52 bound to heat shock proteins may have a role in neurodegeneration by modulating protein folding and aggregation 23 .…”

Section: The Role Of Ppiases In Neurodegenerationmentioning

confidence: 99%

The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

McClements¹,

Annett²,

Yakkundi³

et al. 2015

CMP

View full text Add to dashboard Cite

Peptidyl prolyl isomerases (PPIases) are proteins belonging to the immunophilin family and are characterised by their cis-trans isomerization activity at the X-Pro peptide bond, in addition to their tetratricopeptide repeat (TPR) domain, important for interaction with the molecular chaperone, Hsp90. Due to this unique structure these proteins are able to facilitate proteinprotein interactions which can impact significantly on a range of cellular processes such as cell signalling, differentiation, cell cycle progression, metabolic activity and apoptosis.Malfunction and/or dysregulation of most members of this class of proteins promotes cellular damage and tissue/organ failure, predisposing to ageing and age-related diseases. Many individual genes within the PPIase family are associated with several age-related diseases including cardiovascular diseases (CVDs), atherosclerosis, type II diabetes (T2D), chronic kidney disease (CDK), neurodegeneration, cancer and age-related macular degeneration (AMD), in addition to the ageing process itself. This review will focus on the different roles of PPIases, and their therapeutic/biomarker potential in these age-related vascular diseases.

show abstract

“…F KBP-domain-containing proteins (FKBPs), whose prototypic member is FKBP12, play pivotal roles in cellular signaling, protein folding, and transcription (1)(2)(3)(4). In addition to playing these intrinsic cellular roles, FKBPs mediate the effects of the immunosuppressive drugs FK506 and rapamycin (5,6).…”

mentioning

confidence: 99%

Unique structural features of the AIPL1–FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness

Yadav

Gakhar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

FKBP-domain proteins (FKBPs) are pivotal modulators of cellular signaling, protein folding, and gene transcription. Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a distinctive member of the FKBP superfamily in terms of its biochemical properties, and it plays an important biological role as a chaperone of phosphodiesterase 6 (PDE6), an effector enzyme of the visual transduction cascade. Malfunction of mutant AIPL1 proteins triggers a severe form of Leber congenital amaurosis and leads to blindness. The mechanism underlying the chaperone activity of AIPL1 is largely unknown, but involves the binding of isoprenyl groups on PDE6 to the FKBP domain of AIPL1. We solved the crystal structures of the AIPL1-FKBP domain and its pathogenic mutant V71F, both in the apo form and in complex with isoprenyl moieties. These structures reveal a module for lipid binding that is unparalleled within the FKBP superfamily. The prenyl binding is enabled by a unique "loop-out" conformation of the β4-α1 loop and a conformational "flip-out" switch of the key W72 residue. A second major conformation of apo AIPL1-FKBP was identified by NMR studies. This conformation, wherein W72 flips into the ligand-binding pocket and renders the protein incapable of prenyl binding, is supported by molecular dynamics simulations and appears to underlie the pathogenicity of the V71F mutant. Our findings offer critical insights into the mechanisms that underlie AIPL1 function in health and disease, and highlight the structural and functional diversity of the FKBPs.F KBP-domain-containing proteins (FKBPs), whose prototypic member is FKBP12, play pivotal roles in cellular signaling, protein folding, and transcription (1-4). In addition to playing these intrinsic cellular roles, FKBPs mediate the effects of the immunosuppressive drugs FK506 and rapamycin (5, 6). Binding of FK506 to FKBP12 creates an interface for calcineurin, whereas binding of rapamycin enables interaction with and inhibition of mammalian target of rapamycin; thus, FKBP12 can initiate two distinct immunosuppressive pathways (7). Many FKBPs are peptidylprolylisomerases (PPIases) that catalyze the cis-trans conversion of peptidylprolyl bonds (8). A wealth of structural information on FKBPs and their complexes with drugs has been gathered over the years. A classic FKBP domain fold is comprised of a half-conical sixstranded β-sheet surrounding a short central α-helix. Both FK506 and rapamycin bind within a prominent and highly conserved hydrophobic cavity between the β-sheet and the α-helix (5). These drugs also contact a hairpin loop of ∼20 aa that links β-strands β5 and β6 and hangs over the cavity (Fig. 1C). Surprisingly, other than the fact that this pocket contributes to the PPIase active site (9), very little is known about its physiological significance or its natural ligands. One of the few examples of such ligands is the type I TGFβ receptor, to which FKBP12 binds via its hydrophobic pocket and hairpin loop (10).Notably, one member of the FKBP family is known to play a ...

show abstract

FKBP51 and FKBP52 in signaling and disease

Cited by 224 publications

References 98 publications

Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

Unique structural features of the AIPL1–FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness

Contact Info

Product

Resources

About