Take home lessons from studies of related proteins

Nickson, Adrian A.; Wensley, Beth G.; Clarke, Jane

doi:10.1016/j.sbi.2012.11.009

Cited by 35 publications

(41 citation statements)

References 86 publications

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“…2). These findings contrast with the long held view that this family possesses small, polarized TSEs whose structure is strongly sequence dependent (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Despite the conserved topology, sequence does exert notable effects.…”

Section: Discussionmentioning

confidence: 63%

“…In addition to changes in the TSE, the protein sequence can influence the energy landscape of homologs by altering the energetics of intermediates (2). A partially misfolded intermediate accumulates in the folding of Im7, but not its homolog, Im9 (63,64).…”

Section: Discussionmentioning

confidence: 99%

“…This issue has been investigated by probing how folding transition state ensembles (TSEs) differ for homologous proteins (1,2). Both experimental and computational studies of the α/β homologs Proteins L & G typically identify their TSEs as being polarized, consisting of either the N-or C-terminal hairpin, respectively (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

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confidence: 99%

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Even with nonnative interactions, the updated folding transition states of the homologs Proteins G & L are extensive and similar

Baxa

Adhikari

et al. 2015

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

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Experimental and computational folding studies of Proteins L & G and NuG2 typically find that sequence differences determine which of the two hairpins is formed in the transition state ensemble (TSE). However, our recent work on Protein L finds that its TSE contains both hairpins, compelling a reassessment of the influence of sequence on the folding behavior of the other two homologs. We characterize the TSEs for Protein G and NuG2b, a triple mutant of NuG2, using ψ analysis, a method for identifying contacts in the TSE. All three homologs are found to share a common and near-native TSE topology with interactions between all four strands. However, the helical content varies in the TSE, being largely absent in Proteins G & L but partially present in NuG2b. The variability likely arises from competing propensities for the formation of nonnative β turns in the naturally occurring proteins, as observed in our TerItFix folding algorithm. All-atom folding simulations of NuG2b recapitulate the observed TSEs with four strands for 5 of 27 transition paths [Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) Science 334(6055):517–520]. Our data support the view that homologous proteins have similar folding mechanisms, even when nonnative interactions are present in the transition state. These findings emphasize the ongoing challenge of accurately characterizing and predicting TSEs, even for relatively simple proteins.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Even with nonnative interactions, the updated folding transition states of the homologs Proteins G & L are extensive and similar

Baxa

Adhikari

et al. 2015

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

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“…Following this initial step, the transition towards the fully folded state is fast and efficient [10,11]. Other proteins will follow a hierarchical mechanism, which is characterized by the successive condensation of specific secondary structural units (termed foldons) [12][13][14], while in some protein families (such as the homeodomain) the different members will present mixed folding mechanisms ranging from pure nucleation-condensation to pure hierarchical [15].…”

Section: Introductionmentioning

confidence: 99%

Fold and flexibility: what can proteins' mechanical properties tell us about their folding nucleus?

Sacquin-Mora¹

2015

J. R. Soc. Interface.

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The determination of a protein's folding nucleus, i.e. a set of native contacts playing an important role during its folding process, remains an elusive yet essential problem in biochemistry. In this work, we investigate the mechanical properties of 70 protein structures belonging to 14 protein families presenting various folds using coarse-grain Brownian dynamics simulations. The resulting rigidity profiles combined with multiple sequence alignments show that a limited set of rigid residues, which we call the consensus nucleus, occupy conserved positions along the protein sequence. These residues' side chains form a tight interaction network within the protein's core, thus making our consensus nuclei potential folding nuclei. A review of experimental and theoretical literature shows that most (above 80%) of these residues were indeed identified as folding nucleus member in earlier studies.

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“…Extensive experimental and computational studies have provided significant mechanistic insight into folding pathways (1)(2)(3)(4)(5). These proteins, which fold rapidly, have been shown to possess relatively smooth energy landscapes (6,7).…”

mentioning

confidence: 99%

Knotting and unknotting of a protein in single molecule experiments

Ziegler

Lim

Mandal

et al. 2016

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

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Spontaneous folding of a polypeptide chain into a knotted structure remains one of the most puzzling and fascinating features of protein folding. The folding of knotted proteins is on the timescale of minutes and thus hard to reproduce with atomistic simulations that have been able to reproduce features of ultrafast folding in great detail. Furthermore, it is generally not possible to control the topology of the unfolded state. Single-molecule force spectroscopy is an ideal tool for overcoming this problem: by variation of pulling directions, we controlled the knotting topology of the unfolded state of the 5 2 -knotted protein ubiquitin C-terminal hydrolase isoenzyme L1 (UCH-L1) and have therefore been able to quantify the influence of knotting on its folding rate. Here, we provide direct evidence that a threading event associated with formation of either a 3 1 or 5 2 knot, or a step closely associated with it, significantly slows down the folding of UCH-L1. The results of the optical tweezers experiments highlight the complex nature of the folding pathway, many additional intermediate structures being detected that cannot be resolved by intrinsic fluorescence. Mechanical stretching of knotted proteins is also of importance for understanding the possible implications of knots in proteins for cellular degradation. Compared with a simple 3 1 knot, we measure a significantly larger size for the 5 2 knot in the unfolded state that can be further tightened with higher forces. Our results highlight the potential difficulties in degrading a 5 2 knot compared with a 3 1 knot.knotted proteins | protein folding | single molecule | optical tweezers | ubiquitin C-terminal hydrolase

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Take home lessons from studies of related proteins

Cited by 35 publications

References 86 publications

Even with nonnative interactions, the updated folding transition states of the homologs Proteins G & L are extensive and similar

Even with nonnative interactions, the updated folding transition states of the homologs Proteins G & L are extensive and similar

Fold and flexibility: what can proteins' mechanical properties tell us about their folding nucleus?

Knotting and unknotting of a protein in single molecule experiments

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