Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes

Fischer, Gunter; Aumüller, Tobias

doi:10.1007/s10254-003-0011-3

Cited by 214 publications

(154 citation statements)

References 244 publications

(194 reference statements)

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“…However, the role of a closely related protein, cyclophilin A (CypA), in the formation of cartilage and endochondral bone remains to be elucidated. CypA, the Ppia gene product, is a member of the peptidyl-prolyl isomerase (PPIase) family, catalyzing not only the cis-trans isomerization of peptidyl-prolyl bonds during protein folding but also conformational changes (14). CypA was first identified as the primary intracellular target of the immunosuppressive drug cyclosporine (CsA) (15).…”

Section: Runx2mentioning

confidence: 99%

Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification

Guo

Shen

Kwak

et al. 2015

Molecular and Cellular Biology

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g Recent studies showed that cyclophilin A (CypA) promotes NF-B/p65 nuclear translocation, resulting in enhanced NF-B activity and altered expression of its target genes, such as the Sox9 transcriptional factor, which plays a critical role in chondrogenic differentiation and endochondral ossification. In this report, we unveil the role of CypA in signal-induced chondrogenic differentiation and endochondral ossification. Expression levels of the chondrogenic differentiation markers and transcriptional regulators Sox9 and Runx2 were all significantly lower in CypA knockdown chondrogenic cells than in wild-type cells, indicating that CypA plays a functional role in chondrogenic differentiation. In vitro differentiation studies using micromass cultures of mouse limb bud cells further supported the conclusion that CypA is needed for chondrogenic differentiation. Newborn CypAdeficient pups double stained with alcian blue and alizarin red exhibited generalized, pronounced skeletal defects, while highresolution micro-computed tomography ( Chondrogenesis is an essential process in vertebrates. It leads to the formation of cartilage growth plates, thereby driving bodily growth while providing structural templates and induction signals for the formation of long bones through endochondral ossification (1). On the other hand, defects in chondrogenesis cause various chondrodysostoses and chondrodysplasias, with such skeletal malformations accounting for a significant proportion of human birth defects that often result in embryonic and perinatal lethality (2). To identify the molecular mechanisms that drive chondrocyte differentiation and impact underlying cartilage diseases, the transcriptional mechanisms governing their cartilage-specific expression have been intensely studied. As a general overview, the chondrocyte differentiation pathway corresponds to a succession of major genetic program switches that are likely controlled by a specific set of transcriptional activators, repressors, and associated factors. While some of these factors play essential roles in determining cell fate and differentiation, other factors are found to be mutated in severe diseases of cartilage and bone malformation (3). The framework of the cartilage matrix is a collagen fiber network comprised primarily of type II collagen (Col2) (encoded by the Col2␣1 gene) and secondarily of type IX collagen (encoded by Col9␣1, Col9␣2, and Col9␣3). Collagen type X (Col10) (encoded by Col10␣1) is also produced in abundance, but exclusively by prehypertrophic and hypertrophic chondrocytes (2).Importantly, chondrocyte differentiation requires Sox family transcription factors in the early stages and Runx2 in the late stages (4, 5). In particular, Sox9 has an essential, nonredundant role in specifying the commitment and differentiation of mesenchymal cells toward the chondrogenic lineage in all developing skeletal elements. While Sox9 is turned on in chondrogenic and osteogenic mesenchymal cells prior to condensation and remains highly expressed in prechondrocytes...

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Section: Runx2mentioning

confidence: 99%

Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification

Guo

Shen

Kwak

et al. 2015

Molecular and Cellular Biology

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“…1A) is an intrinsically slow reaction that depends on the nature of the amino acid Xaa (1)(2)(3). It determines the rates of many protein folding reactions (4)(5)(6), is used as a molecular switch (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), and is catalyzed by prolyl isomerases (17)(18)(19)(20)(21). Most of the prolyl isomerases that assist in cellular protein folding contain catalytic domains that are homologous to human FKBP12 (FK-506 binding protein of 12 kDa; Fig.…”

mentioning

confidence: 99%

Chaperone domains convert prolyl isomerases into generic catalysts of protein folding

Jakob

Žoldák

Aumüller

et al. 2009

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

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The cis/trans isomerization of peptide bonds before proline (prolyl bonds) is a rate-limiting step in many protein folding reactions, and it is used to switch between alternate functional states of folded proteins. Several prolyl isomerases of the FK506-binding protein family, such as trigger factor, SlyD, and FkpA, contain chaperone domains and are assumed to assist protein folding in vivo. The prolyl isomerase activity of FK506-binding proteins strongly depends on the nature of residue Xaa of the Xaa-Pro bond. We confirmed this in assays with a library of tetrapeptides in which position Xaa was occupied by all 20 aa. A high sequence specificity seems inconsistent with a generic function of prolyl isomerases in protein folding. Accordingly, we constructed a library of protein variants with all 20 aa at position Xaa before a rate-limiting cis proline and used it to investigate the performance of trigger factor and SlyD as catalysts of proline-limited folding. The efficiencies of both prolyl isomerases were higher than in the tetrapeptide assays, and, intriguingly, this high activity was almost independent of the nature of the residue before the proline. Apparently, the almost indiscriminate binding of the chaperone domain to the refolding protein chain overrides the inherently high sequence specificity of the prolyl isomerase site. The catalytic performance of these folding enzymes is thus determined by generic substrate recognition at the chaperone domain and efficient transfer to the active site in the prolyl isomerase domain.folding catalysis ͉ folding helpers ͉ folding mechanism ͉ SlyD ͉ trigger factor T he cis/trans isomerization of peptide bonds before proline (Xaa-Pro or prolyl bonds; Fig. 1A) is an intrinsically slow reaction that depends on the nature of the amino acid Xaa (1-3). It determines the rates of many protein folding reactions (4-6), is used as a molecular switch (7-16), and is catalyzed by prolyl isomerases (17-21). Most of the prolyl isomerases that assist in cellular protein folding contain catalytic domains that are homologous to human FKBP12 (FK-506 binding protein of 12 kDa; Fig. 1B) and chaperone domains, which interact transiently with non-native proteins (Fig. 1B). The trigger factor (22-25) and SlyD [product of the slyD (sensitive-to lysis) gene, a cytosolic Escherichia coli chaperone] (26-29) belong to this family of folding enzymes. The chaperone domain of SlyD (the ''insertin-flap'' or IF domain) shows a unique fold (30) and is structurally not related to other chaperones. The chaperone domain of trigger factor shows similarities with prefoldin (31)and SurA (32). FkpA (periplasmic FKBP of E. coli) (33-35) of prokaryotes and FKBP52 of eukaryotes (36) display similar combinations of prolyl isomerase and chaperone domains.FKBP-type prolyl isomerases are highly specific with regard to residue Xaa before the proline (37-39). An initial characterization of human FKBP12 with various proline-containing tetrapeptides and a protease-coupled assay (17) indicated that it catalyzes isomerizati...

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“…It has long been known that prolyl isomerizations play important roles as rate-determining steps in protein folding, but more recently, evidence has accumulated that prolyl isomerizations in folded proteins are involved in a multitude of regulatory processes (22)(23)(24)(25)(26)(27). Also, it was proposed that the time course of proline-controlled signaling events is modulated by prolyl isomerases such as cyclophilin or Pin1 (28,29).…”

Section: Discussionmentioning

confidence: 99%

Initiation of Phage Infection by Partial Unfolding and Prolyl Isomerization

Hoffmann-Thoms

Weininger

Eckert

et al. 2013

Journal of Biological Chemistry

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Background: Bacteriophage fd is activated for infection by partial unfolding and prolyl isomerization. Results: NMR spectroscopy localized Pro-213-coupled unfolding to regions of the interdomain hinge of the phage gene-3-protein.Conclusion: Pro-213 regulates phage infectivity by a specific long-range effect on the conformational stability of the gene-3-protein.Significance: A proline switch controls the biological function in a remote part of a protein.

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Regulation of peptide bond cis/trans isomerization by enzyme catalysis and its implication in physiological processes

Cited by 214 publications

References 244 publications

Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification

Novel Role for Cyclophilin A in Regulation of Chondrogenic Commitment and Endochondral Ossification

Chaperone domains convert prolyl isomerases into generic catalysts of protein folding

Initiation of Phage Infection by Partial Unfolding and Prolyl Isomerization

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