Early Folding Events Protect Aggregation-Prone Regions of a β-Rich Protein

Budyak, Ivan L.; Krishnan, Beena; Marcelino-Cruz, Anna Marie; Ferrolino, Mylene C.; Zhuravleva, Anastasia; Gierasch, Lila M.

doi:10.1016/j.str.2013.01.013

Cited by 15 publications

(47 citation statements)

References 59 publications

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“…These proteins are small- to medium-sized (DHFR: 159 amino acids; CRABP1: 137 amino acids; RA114: 258 amino acids) and monomeric (Figure 2). That each of these mutants is less stable than the corresponding wild type protein is demonstrated by their susceptibilities to urea denaturation for m-EcDHFR and m-RA114 (Figure S1A, B), and was reported previously for m-MmCRABP1 (Budyak et al, 2013). …”

Section: Resultssupporting

confidence: 79%

Individual and Collective Contributions of Chaperoning and Degradation to Protein Homeostasis in E. coli

et al. 2015

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SUMMARY The folding fate of a protein in vivo is determined by the interplay between a protein’s folding energy landscape and the actions of the proteostasis network, including molecular chaperones and degradation enzymes. The mechanisms of individual components of the E. coli proteostasis network have been studied extensively, but much less is known about how they function as a system. We used an integrated experimental and computational approach to quantitatively analyze the folding outcomes (native folding vs. aggregation vs. degradation) of three test proteins biosynthesized in E. coli under a variety of conditions. Overexpression of the entire proteostasis network benefited all three test proteins, but the effect of upregulating individual chaperones or the major degradation enzyme, Lon, varied for proteins with different biophysical properties. In sum, the impact of the E. coli proteostasis network is a consequence of concerted action by the Hsp70 system (DnaK/DnaJ/GrpE), the Hsp60 system (GroEL/GroES), and Lon.

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Section: Resultssupporting

confidence: 79%

Individual and Collective Contributions of Chaperoning and Degradation to Protein Homeostasis in E. coli

et al. 2015

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“…We note in passing that the presence of well populated intermediates such as the one present in stefin-B can also lead to the exposure of aggregation-prone sequences and amyloid formation. [8][9]17,58 Here, we inferred the connection between the domain-swapping of stefin-B and its function by using the structure of its folding intermediate. However, proteins that do not populate detectable 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 23 amounts of intermediates also domain-swap 59 and such domain-swapping can also be understood using information about partially folded structural ensembles [60][61] (of which intermediate ensembles are a subset).…”

Section: Functional Residues and Folding Cooperativity Mutational Exmentioning

confidence: 99%

Protein Domain-Swapping Can Be a Consequence of Functional Residues

Mascarenhas

Gosavi

2016

J. Phys. Chem. B

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Monomer topology has been implicated in domain-swapping, a potential first step on the route to disease-causing protein aggregation. Despite having the same topology (β1-α1-β2-β3-β4-β5), the cysteine protease inhibitor stefin-B domain swaps more readily than a single-chain variant of the heterodimeric sweet protein monellin (scMn). Here, we computationally study the folding of stefin-B and scMn in order to understand the molecular basis for the difference in their domain-swapping propensities. In agreement with experiments, our structure-based simulations show that scMn folds cooperatively without the population of an intermediate while stefin-B populates an equilibrium intermediate state. Since the simulation intermediate has only one domain structured (β3-β4-β5), it can directly lead to domain-swapping. Using computational variants of stefin-B, we show that the population of this intermediate is caused by regions of stefin-B that have been implicated in protease inhibition. We also find that the protease-binding regions are located on two structural elements and localized in space. In contrast, the residues that contribute to the sweetness of monellin are not localized to a few structural elements but are distributed over the protein fold. We conclude that the distributed functional residues of monellin do not induce large local perturbations in the protein structure, eliminating the formation of folding intermediates and in turn domain-swapping. On the other hand, the localized protease-binding regions of stefin-B promote the formation of a folding intermediate which can lead to domain-swapping. Thus, domain-swapping can be a direct consequence of the constraints that function imposes on the protein structure.

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“…Both may be protective in cells. Additionally, recent work has suggested that the folding mechanism of CRABP1 protects aggregation-prone sequences early in the formation of native structure, providing a neat mechanism of minimizing the risk of aggregation 22 .…”

Section: Ilbps Dynamically Open To Bind Hydrophobic Substratesmentioning

confidence: 99%

“…Extensive studies of the folding and aggregation of CRABP1 have been performed 21,22,32–36 . This has led to intriguing linkages: CRABP1 folds via multiple kinetic steps in which early hydrophobic collapse occurs in a few milliseconds along with formation of its helix-loop-helix motif.…”

Section: Ilbps Dynamically Open To Bind Hydrophobic Substratesmentioning

confidence: 99%

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Energy landscapes of functional proteins are inherently risky

et al. 2014

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Evolutionary pressure for protein function leads to unavoidable sampling of conformational states that are at risk of misfolding and aggregation. The resulting tension between functional requirements and the risk of misfolding and/or aggregation in the evolution of proteins is becoming more and more apparent. One outcome of this tension is sensitivity to mutation, in which only subtle changes in sequence that may be functionally advantageous can tip the delicate balance toward protein aggregation. Similarly, increasing the concentration of aggregation-prone species by reducing the ability to control protein levels or compromising protein folding capacity engenders increased risk of aggregation and disease. In this Perspective, we describe examples that epitomize the tension between protein functional energy landscapes and aggregation risk. Each case illustrates how the energy landscapes for the at-risk proteins are sculpted to enable them to perform their functions and how the risks of aggregation are minimized under cellular conditions using a variety of compensatory mechanisms.

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Early Folding Events Protect Aggregation-Prone Regions of a β-Rich Protein

Cited by 15 publications

References 59 publications

Individual and Collective Contributions of Chaperoning and Degradation to Protein Homeostasis in E. coli

Individual and Collective Contributions of Chaperoning and Degradation to Protein Homeostasis in E. coli

Protein Domain-Swapping Can Be a Consequence of Functional Residues

Energy landscapes of functional proteins are inherently risky

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