Genomic Organization of Mouse and Human 65 kDa FK506-Binding Protein Genes and Evolution of the FKBP Multigene Family

doi:10.1006/geno.2002.6777

Genomics

Volume 79, Issue 6, June 2002, Pages 881-889

https://doi.org/10.1006/geno.2002.6777 Get rights and content

Abstract

FK506-binding proteins (FKBPs) are peptidyl–prolyl cis/trans isomerases PPIases) that bind the immunosuppressive drug FK506. Of the many eukaryotic FKBPs that have been identified, FKBP65 is an endoplasmic reticulum-localized protein that associates with tropoelastin in the secretory pathway. Unlike any other FKBP characterized so far, FKBP65 is developmentally regulated and may be intimately involved in organogenesis. Here, we report the isolation, sequencing, and genomic organization of the mouse FKBP65 gene (Fkbp10) and provide a comparison with the human ortholog. Mouse Fkbp10 contains 10 exons and 9 introns encompassing 8.5 kb. The exon–intron organization of Fkbp10 displays a pattern of repetition that reflects the coding sequence of the four PPIase, or FK506-binding, domains present in the mature protein. The exon organization of the PPIase domains differs from that of the other FKBP family members. The evolution of the FKBP65 gene and other members of the FKBP multigene family were therefore investigated from a taxonomically diverse array of prokaryotic and eukaryotic taxa. These analyses suggest that the FKBP multigene family emerged early in the evolutionary history of eukaryotes, and during that time some members, including the FKBP65 gene, have experienced gene elongation by means of PPIase domain duplication.

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FK506 binding proteins (FKBP) are multifunctional proteins highly conserved across the species and abundantly expressed in the cell. In addition to a well-established role in immunosuppression, FKBPs modulate several signal transduction pathways in the cell, due to their isomerase activity and the capability to interact with other proteins, inducing changes in conformation and function of protein partners. Increasing literature data support the concept that FKBPs control cancer related pathways.
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Genome-wide identification and analysis of FK506-binding protein family gene family in strawberry (Fragaria×ananassa)
2014, Gene
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According to the conserved domain, subcellular location and phylogenetic analysis, FaFKBPa could be a member of FaFKBP12. Gene duplication was the main effect in the FKBP gene family in different species, and FKBPs emerged through domain duplication and exon shuffling events early in eukaryotic evolution (Galat, 2004; Patterson et al., 2002). In plants, FKBPs are crucial for regulating normal growth and development, and for coping with stress conditions, both fundamental considerations in modern farming.
The FK506 binding proteins (FKBPs) are abundant and ubiquitous proteins belonging to the large peptidyl-prolylcis-trans isomerase superfamily. FKBPs are known to be involved in many biological processes including hormone signaling, plant growth, and stress responses through a chaperone or an isomerization of proline residues during protein folding. The availability of complete strawberry genome sequences allowed the identification of 23 FKBP genes by HMMER and blast analysis. Chromosome scaffold locations of these FKBP genes in the strawberry genome were determined and the protein domain and motif organization of FaFKBPs analyzed. The phylogenetic relationships between strawberry FKBPs were also assessed. The expression profiles of FaFKBPs genes results revealed that most FaFKBPs were expressed in all tissues, while a few FaFKBPs were specifically expressed in some of the tissues. These data not only contribute to some better understanding of the complex regulation of the strawberry FKBP gene family, but also provide valuable information for further research in strawberry functional genomics.
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Bruck syndrome (BS) is an autosomal recessive disorder which has skeletal features related to osteogenesis imperfecta (OI) and has traditionally been classified as an OI variant. A characteristic feature of Bruck syndrome is the presence of multiple joint contractures that are congenital and the cause of functional impairment in many patients. Bruck syndrome is a rare cause of bone disease, even within the OI category, perhaps accounting for 1% of the OI population. Bruck syndrome 1 (BS1) is localized to chromosome 17q21.2 and results from mutations in the molecular chaperone, FKBP65. Mutations in FKBP65 also produce moderate to severe OI without contractures. Bruck syndrome 2 (BS2) localizes to chromosome 3 and is due to mutations in PLOD2, which encodes the telopeptide lysyl hydroxylase 2 (LH2). Both proteins have been shown to be involved in the crosslinking of telopeptides in type I collagen. Treatment response data to bisphosphonates is limited in Bruck patients compared to OI patients with type I collagen mutations, but has been used.
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2012, FEBS Letters
Citation Excerpt :
FKBPs are characterised by the inclusion of at least one FK506-binding domain (FKBd), which is the receptor site for proline and proline analogues such as FK506 and rapamycin, and the active site for PPIase catalysis. The FKBd sequence of approximately 110 amino acids (Fig. 1) adopts a well-conserved tertiary structure [12–14], primarily containing six anti-parallel beta sheets connected by a number of solvent-exposed loops, one of which contains a short alpha helix (Fig. 2). The beta sheets form a concave surface opposite the helix and hydrophobic sidechains projected towards the protein core create a hydrophobic cavity that accommodates proline [15].
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Regular ArticleGenomic Organization of Mouse and Human 65 kDa FK506-Binding Protein Genes and Evolution of the FKBP Multigene Family

Abstract

FEBS Lett.

Gene

J. Biol. Chem.

Genomics

Genomics

Gene

Curr. Opin. Struct. Biol.

Sequence diversification of the FK506-binding proteins in several different genomes

Eur. J. Biochem.

The cell cycle, signal transduction, and immunophilins-ligand complexes

Acc. Chem. Res.

Cellular functions of immunophilins

Physiol. Rev.

Immunophilins: beyond immunosuppression

J. Med. Chem.

Folding of ribonuclease T1. 2. Kinetic models for the folding and unfolding reactions

Biochemistry

Identification of tropoelastin as a ligand for the 65-kD FK506-binding protein, FKBP65, in the secretory pathway

J. Cell Biol.

Developmental regulation of FKBP65: an ER-localized extracellular matrix binding-protein

Mol. Biol. Cell

Structure-function relationships in the FK506-binding protein (FKBP) family of peptidyl-prolyl cis-trans isomerases

Biochem. J.

Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex

Science

Archaeal peptidyl prolyl cis-trans isomerases (PPIases)

Front. Biosci.

Regular Article
Genomic Organization of Mouse and Human 65 kDa FK506-Binding Protein Genes and Evolution of the FKBP Multigene Family