Neurospora crassa FKBP22 Is a Novel ER Chaperone and Functionally Cooperates with BiP

Tremmel, Dirk; Tropschug, Maximilian

doi:10.1016/j.jmb.2007.01.092

Cited by 15 publications

(20 citation statements)

References 77 publications

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“…Neurospora crassa FKBP22 was reported to form a complex with BiP and other chaperones (41,67). However, this FKBP22 and the mammalian FKBP22 are structurally distinct except for the FKBP domain.…”

Section: Discussionmentioning

confidence: 99%

A Substrate Preference for the Rough Endoplasmic Reticulum Resident Protein FKBP22 during Collagen Biosynthesis

Ishikawa

Bächinger

2014

Journal of Biological Chemistry

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Background: Procollagen biosynthesis requires a large number of foldases, chaperones, and modifying enzymes. Results: FKBP22 is a foldase and chaperone that interacts with a subset of collagens. Conclusion: Collagen type-specific chaperones and foldases exist in the rER. Significance: The lack of collagen type-specific rER proteins can lead to broader or overlapping phenotypes of connective tissue disorders.

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Section: Discussionmentioning

confidence: 99%

A Substrate Preference for the Rough Endoplasmic Reticulum Resident Protein FKBP22 during Collagen Biosynthesis

Ishikawa

Bächinger

2014

Journal of Biological Chemistry

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“…FKBP22 has both PPIase activity and chaperone activity like FKBP65, however, the chaperone activity is completely blocked by the addition of FK506 (20). In contrast, FKBP65 retains its chaperone activity, probably due to the presence of four FKBP domains, of which only one can bind FK506 (12).…”

Section: Discussionmentioning

confidence: 99%

“…FKBP13, another rER-resident FKBP, was shown to be up-regulated by the accumulation of unfolded proteins (17,18), and recently FKBP22 was shown to be an rER chaperone that interacts with BiP (19,20). Why does FKBP65 interact with gelatinSepharose and what is the role of FKBP65 during collagen biosynthesis?…”

mentioning

confidence: 99%

The Rough Endoplasmic Reticulum-resident FK506-binding Protein FKBP65 Is a Molecular Chaperone That Interacts with Collagens

Ishikawa

Vranka

Wirz

et al. 2008

Journal of Biological Chemistry

109

100

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Here we show that FKBP65 is a monomer in solution and acts as a chaperone molecule when tested with two classic chaperone assays: FKBP65 inhibits the thermal aggregation of citrate synthase and is active in the denatured rhodanese refolding and aggregation assay. The chaperone activity is comparable to that of protein-disulfide isomerase, a well characterized chaperone. FKBP65 delays the in vitro fibril formation of type I collagen, indicating that FKBP65 is also able to interact with triple helical collagen, and acts as a collagen chaperone.The FK506-binding protein FKBP65 is a member of the FK506-binding protein (FKBP) 2 class of immunophilins. Immunophilins are intracellular receptors of two immunosuppressant drugs cyclosporine A and FK506, and these receptors were divided into two classes in accordance with their binding ability of the immunosuppressant drugs. Proteins that bind to cyclosporine A are called the cyclophilins. FKBPs bind FK506 and are highly conserved and found in bacteria, yeast, and many tissues of higher eukaryotes. Almost every cellular compartment contains a member of this protein family. The FKBP class includes FKBP9, FKBP12, FKBP13, FKBP25, FKBP52, FKBP54, FKBP60, and FKBP65. All these proteins contain the binding motif for FK506. Both protein families have peptidylprolyl cistrans-isomerase (PPIase) activity.FKBP65 was first identified in mouse NIH3T3 fibroblasts (1), and it consists of four basic FKBP13 domains. It was originally thought that FKBP65 interacts with c-Raf-1 (2), in analogy to the function of FKBP52 in stabilizing the glucocorticoid receptor (3) or FKBP12 in stabilizing the ryanodine (4) or the inositol 1,4,5-triphosphate receptor (5). However, it was shown later that FKBP65 is a luminal rough endoplasmic reticulum (rER)-resident protein that co-localized with tropoelastin (6). It was suggested that the PPIase activity of FKBP65 is important for the folding of the proline-rich tropoelastin (7).The biosynthesis of collagens involves a large number of post-translational modifications in which many different rERresident proteins are involved (8). After the translocation of the growing polypeptide chains of procollagens into the rER, proline residues become 4-hydroxylated by prolyl 4-hydroxlase. 4-Hydroxylation of proline residues increases the stability of the triple helix and is a key element in the folding of the triple helix. Prolyl 4-hydroxylase requires an unfolded chain as a substrate. The chain selection and association for triple helix formation is determined by the C-terminal propeptides in fibrillar collagens. Premature association between procollagen chains is thought to be prevented by chaperones such as PDI, BiP/ GRP78, GRP94, and HSP47 and collagen modifying enzymes until the biosynthesis of the individual chain is completed. Additional modifications are the 3-hydroxylation of proline residues by the P3H1/CRTAP/cyclophilin B complex, the hydroxylation of lysine residues by lysyl hydroxylases and glycosylation. The chains are then selected, and trimers are for...

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“…Five of these proteins contain two EF-hand Ca 2+ -binding domains (only FKBP13 lacks these domains). FKBP22 and FKBP23 have been shown to bind GRP78/BiP chaperone in a Ca 2+ -dependent manner, potentially playing a role in regulating chaperone activity (Tremmel and Tropschug 2007;Wang et al 2007). FKBP65 (encoded by gene FKBP10) is the largest of the FK506-binding proteins, containing four PPIase domains, two C-terminal EF-hand domains, and a C-terminal HEEL domain for ER localization.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress or mutation of an EF-hand Ca2+-binding domain directs the FKBP65 rotamase to an ERAD-based proteolysis

Murphy

Ramirez

Trinh

et al. 2011

Cell Stress and Chaperones

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FKBP65 is an endoplasmic reticulum (ER)-localized chaperone and rotamase, with cargo proteins that include tropoelastin and collagen. In humans, mutations in FKBP65 have recently been shown to cause a form of osteogenesis imperfecta (OI), a brittle bone disease resulting from deficient secretion of mature type I collagen. In this work, we describe the rapid proteolysis of FKBP65 in response to ER stress signals that activate the release of ER Ca 2+ stores. A large-scale screen for stress-induced cellular changes revealed FKBP65 proteins to decrease within 6-12 h of stress activation. Inhibiting IP 3 R-mediated ER Ca 2+ release blocked this response. No other ER-localized chaperone and folding mediators assessed in the study displayed this phenomenon, indicating that this rapid proteolysis of folding mediator is distinctive. Imaging and cellular fractionation confirmed the localization of FKBP65 (72 kDa glycoprotein) to the ER of untreated cells, a rapid decrease in protein levels following ER stress, and the corresponding appearance of a 30-kDa fragment in the cytosol. Inhibition of the proteasome during ER stress revealed an accumulation of FKBP65 in the cytosol, consistent with retrotranslocation and a proteasome-based proteolysis. To assess the role of Ca 2+ -binding EF-hand domains in FKBP65 stability, a recombinant FKBP65-GFP construct was engineered to ablate Ca 2+ binding at each of two EF-hand domains. Cells transfected with the wild-type construct displayed ER localization of the FKBP65-GFP protein and a proteasome-dependent proteolysis in response to ER stress. Recombinant FKBP65-GFP carrying a defect in the EF1 Ca 2+ -binding domain displayed diminished protein in the ER when compared to wild-type FKBP65-GFP. Proteasome inhibition restored mutant protein to levels similar to that of the wild-type FKBP65-GFP. A similar mutation in EF2 did not confer FKBP65 proteolysis. This work supports a model in which stress-induced changes in ER Ca 2+ stores induce the rapid proteolysis of FKBP65, a chaperone and folding mediator of collagen and tropoelastin. The destruction of this protein may identify a cellular strategy for replacement of protein folding machinery following ER stress. The implications for stress-induced changes in the handling of aggregateprone proteins in the ER-Golgi secretory pathway are discussed.

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Neurospora crassa FKBP22 Is a Novel ER Chaperone and Functionally Cooperates with BiP

Cited by 15 publications

References 77 publications

A Substrate Preference for the Rough Endoplasmic Reticulum Resident Protein FKBP22 during Collagen Biosynthesis

A Substrate Preference for the Rough Endoplasmic Reticulum Resident Protein FKBP22 during Collagen Biosynthesis

The Rough Endoplasmic Reticulum-resident FK506-binding Protein FKBP65 Is a Molecular Chaperone That Interacts with Collagens

Endoplasmic reticulum stress or mutation of an EF-hand Ca2+-binding domain directs the FKBP65 rotamase to an ERAD-based proteolysis

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