Control of protein function by prolyl isomerization

Schmidpeter, Philipp A. M.; Koch, Johanna R.; Schmid, Franz X.

doi:10.1016/j.bbagen.2014.12.019

Cited by 37 publications

(41 citation statements)

References 109 publications

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“…Cis-trans isomerization of peptidyl-prolyl bonds in the context of a native state was observed previously in other folded proteins and, in some cases, was shown to be functionally important and act as a molecular switch 45-49 . The functional significance of the cis-trans isomerization of P847 in 3FN3, however, is not clear at this point, and the heterogeneity may just be a consequence of the relatively low stability of 3FN3 (see below) and the inability to stabilize one isomer strongly over the other 48, 49 .…”

Section: Resultssupporting

confidence: 61%

“…The functional significance of the cis-trans isomerization of P847 in 3FN3, however, is not clear at this point, and the heterogeneity may just be a consequence of the relatively low stability of 3FN3 (see below) and the inability to stabilize one isomer strongly over the other 48, 49 . Interestingly, a number of the FN3 domains in fibronectin contain a proline residue at the position equivalent to P847 (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Structure and Unfolding of the Third Type III Domain from Human Fibronectin

et al. 2015

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Fibronectin is a modular extracellular matrix protein that is essential for vertebrate development. The 3rd type III domain (3FN3) in fibronectin interacts with other parts of fibronectin and with anastellin, a protein fragment that causes fibronectin aggregation. 3FN3 opens readily both as an isolated domain in solution and when part of fibronectin in stretched fibrils, and it was proposed that this opening is important for anastellin binding. We determined the structure of 3FN3 using nuclear magnetic resonance spectroscopy and we investigated its stability, folding and unfolding. Similar to most other FN3 domains, 3FN3 contains two antiparallel β-sheets that are composed of three (A, B and E) and four (C, D, F and G) β-strands, respectively, and are held together by a conserved hydrophobic interface. Cis-trans isomerization of P847 at the end of β-strand C leads to observable conformational heterogeneity in 3FN3, with a cis peptide bond present in almost one quarter of the molecules. The chemical stability of 3FN3 is relatively low, but the folding rate constant in the absence of denaturant is in the same range as those of other, more stable FN3 domains. Interestingly, the unfolding rate constant in the absence of denaturant is several orders of magnitude higher than the unfolding rate constants of other FN3 domains investigated to date. This unusually fast rate is comparable to the rate of 3FN3 binding to anastellin at saturating anastellin concentrations, consistent with the model that 3FN3 has to unfold in order to interact with anastellin.

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Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Structure and Unfolding of the Third Type III Domain from Human Fibronectin

et al. 2015

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“…The isomeric state of proline residues controls myriad biomolecular processes, including protein folding, domain oligomerization, ion channel gating, signaling by multi-domain proteins and the epigenetic code (Nicholson and De, 2011; Sarkar et al, 2011; Schmidpeter et al, 2014; Howe et al, 2014). The population of prolyl cis and trans isomers is often controlled by prolyl isomerases (Schiene-Fischer, 2014).…”

Section: Discussionmentioning

confidence: 99%

Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis

et al. 2015

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SUMMARY The cytosolic fraction of the tumor suppressor p53 activates the apoptotic effector protein BAX to trigger apoptosis. Here we report that p53 activates BAX through a mechanism different from that associated with activation by BH3 only proteins (BIM and BID). We observed that cis-trans isomerization of proline 47 (Pro47) within p53, an inherently rare molecular event, was required for BAX activation. The prolyl isomerase Pin1 enhanced p53-dependent BAX activation by catalyzing cis-trans interconversion of p53 Pro47. Our results reveal a signaling mechanism whereby proline cis-trans isomerization in one protein triggers conformational and functional changes in a downstream signaling partner. Activation of BAX through the concerted action of cytosolic p53 and Pin1 may integrate cell stress signals to induce a direct apoptotic response.

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“…They can serve also as slow molecular switches or timers in the regulation of protein function [4][5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%