Stabilizing effect of knots on proteins

Sułkowska, Joanna I.; Sułkowski, Piotr; Szymczak, Piotr; Cieplak, Marek

doi:10.1073/pnas.0805468105

Cited by 134 publications

(153 citation statements)

References 38 publications

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“…To further understand the effect of the knot, we rebuilt protein 1o6d into a very similar structure, but without knot topology (23). As expected, under similar simulation conditions, the number of successful folding events increases substantially to Ϸ73%.…”

Section: Discussionmentioning

confidence: 73%

Dodging the crisis of folding proteins with knots

Sułkowska

Sułkowski

Onuchic

2009

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

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161

217

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Proteins with nontrivial topology, containing knots and slipknots, have the ability to fold to their native states without any additional external forces invoked. A mechanism is suggested for folding of these proteins, such as YibK and YbeA, that involves an intermediate configuration with a slipknot. It elucidates the role of topological barriers and backtracking during the folding event. It also illustrates that native contacts are sufficient to guarantee folding in Ϸ1-2% of the simulations, and how slipknot intermediates are needed to reduce the topological bottlenecks. As expected, simulations of proteins with similar structure but with knot removed fold much more efficiently, clearly demonstrating the origin of these topological barriers. Although these studies are based on a simple coarse-grained model, they are already able to extract some of the underlying principles governing folding in such complex topologies. molecular dynamics ͉ slipknots ͉ backtracking ͉ topological barriers D uring the past 2 decades, a joint theoretical and experimental effort has largely advanced the quantitative understanding of the protein folding mechanism. Most small-and intermediate-size proteins live on a minimally frustrated funnel-like energy landscape, which allows fast and robust folding (1-3). Because proteins have been able to solve the energy problem, the final challenge is the structural complexity of the protein folding motifs. Most proteins avoid complex topologies, but recent discoveries have shown that some proteins are actually able to fold into nontrivial topologies where the main chain folds into a knotted conformation (4-6). Although these ''knotted'' folding motifs have been observed, we still have to face the challenging question of how the protein overcomes the kinetic barrier associated with the search of the knotted conformation. We suggest a possible mechanism where the knot formation is preceded by a conformation called a ''slipknot.'' A slipknot is topologically similar to a knot, except that an internal knot is effectively undone as the pathway of the backbone folds back on itself. The fact that such slipknots have already been observed in some protein final structures (7) adds support to this suggestion.This folding mechanism is explored in the context of the two most experimentally investigated knotted families of proteins, Haemophilus influenzae YibK and Escherichia coli YbeA, which are homodimeric ␣/␤-knot methyltransferases (MTases). A schematic representation of these proteins is shown in Fig. 1, [see also supporting information (SI) Fig. S1]. It has been shown experimentally that both these proteins unfold spontaneously and reversibly on addition of chemical denaturant (8-11) and they are able to fold even when additional domains are attached to one or both termini (12). In very recent experimental work (13), based on analysis of the effect of mutations in the knotted region of the protein, a folding model for YibK was also proposed. In this model the threading of the polypeptide chain and fo...

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Section: Discussionmentioning

confidence: 73%

Dodging the crisis of folding proteins with knots

Sułkowska

Sułkowski

Onuchic

2009

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

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161

217

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“…The fact that all of these proteins show very similar knotting fingerprints despite their large sequence divergence suggests that this particular knotting offers an evolutionary advantage. A number of papers have shown that the formation of knots and slipknots increases protein stability (7,12) because there are protein subchains that embrace other subchains in a stable manner. In this context, one is tempted to speculate that, in case of transporter proteins forming a transmembrane channel, the channel may be held together more tightly when α-helices forming it are strapped together by a slipknot loop embracing several of the helices.…”

Section: Coupled Figure-eight Trefoil Slipknotmentioning

confidence: 99%

“…In general, knots in proteins are orders of magnitude less frequent than would be expected for random polymers with similar length, compactness, and flexibility (3). In principle, the polypeptide chains folding into knotted native protein structures encounter more kinetic difficulties than unknotted proteins (4)(5)(6)(7)(8)(9)(10)(11)(12). Therefore, it is believed that knotted protein structures were, in part, eliminated during evolution because proteins that fold slowly and/or nonreproducibly should be evolutionarily disadvantageous for the hosting organisms.…”

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confidence: 99%

Conservation of complex knotting and slipknotting patterns in proteins

Sułkowska

Rawdon

Millett

et al. 2012

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

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222

229

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While analyzing all available protein structures for the presence of knots and slipknots, we detected a strict conservation of complex knotting patterns within and between several protein families despite their large sequence divergence. Because protein folding pathways leading to knotted native protein structures are slower and less efficient than those leading to unknotted proteins with similar size and sequence, the strict conservation of the knotting patterns indicates an important physiological role of knots and slipknots in these proteins. Although little is known about the functional role of knots, recent studies have demonstrated a proteinstabilizing ability of knots and slipknots. Some of the conserved knotting patterns occur in proteins forming transmembrane channels where the slipknot loop seems to strap together the transmembrane helices forming the channel.protein knots | knot theory | topology T here are increasing numbers of known proteins that form linear open knots in their native folded structure (1, 2). In general, knots in proteins are orders of magnitude less frequent than would be expected for random polymers with similar length, compactness, and flexibility (3). In principle, the polypeptide chains folding into knotted native protein structures encounter more kinetic difficulties than unknotted proteins (4-12). Therefore, it is believed that knotted protein structures were, in part, eliminated during evolution because proteins that fold slowly and/or nonreproducibly should be evolutionarily disadvantageous for the hosting organisms. Nevertheless, there are several families of proteins that reproducibly form simple knots, complex knots, and slipknots (1, 2). In these proteins, the disadvantage of less efficient folding may be balanced by a functional advantage connected with the presence of these knots. Numerous experimental (13-16) and theoretical (17-27) studies have been devoted to understanding the precise nature of the structural and functional advantages created by the presence of these knots in protein backbones. It has been proposed that in some cases the protein knots and slipknots provide a stabilizing function that can act by holding together certain protein domains (4). In the majority of cases, however, one is unable to determine the precise structural and functional advantages provided by the presence of knots.To shed light on the function and formation of protein knots, we performed a thorough characterization of knotting within protein structures deposited in the Protein Data Bank (PDB) (28) by creating a precise mapping of the position and size of the knotted and slipknotted domains and knot tails (1, 2). We identified the types of knots that are formed by the backbone of the entire polypeptide chain and also by all continuous backbone portions of a given protein (1, 2). To characterize the knotting of proteins with linear backbones, one needs to set aside the orthodox rule of knot theory that states that all linear chains are unknotted because, by a continuous deformation,...

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“…[41][42][43] The investigation of the effects of topological constraints on globular polymers, both in and out of equilibrium, is also expected to be a key to understand chromosomal architecture. 44,45 In the present work we considerably extend and discuss in further detail some of the results presented in Refs.…”

Section: Introductionmentioning

confidence: 99%

Knotted Globular Ring Polymers: How Topology Affects Statistics and Thermodynamics

2014

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The statistical mechanics of a long knotted collapsed polymer is determined by a free-energy with a knot-dependent subleading term, which is linked to the length of the shortest polymer that can hold such knot. The only other parameter depending on the knot kind is an amplitude such that relative probabilities of knots do not vary with the temperature T , in the limit of long chains. We arrive at this conclusion by simulating interacting self-avoiding rings at low T on the cubic lattice, both with unrestricted topology and with setups where the globule is divided by a slip link in two loops (preserving their topology) which compete for the chain length, either in contact or separated by a wall as for translocation through a membrane pore. These findings suggest that in macromolecular environments there may be entropic forces with a purely topological origin, whence portions of polymers holding complex knots should tend to expand at the expense of significantly shrinking other topologically simpler portions. 1

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Stabilizing effect of knots on proteins

Cited by 134 publications

References 38 publications

Dodging the crisis of folding proteins with knots

Dodging the crisis of folding proteins with knots

Conservation of complex knotting and slipknotting patterns in proteins

Knotted Globular Ring Polymers: How Topology Affects Statistics and Thermodynamics

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