Infinite Assembly of Folded Proteins in Evolution, Disease, and Engineering

Garcia‐Seisdedos, Hector; Villegas, José A.; Levy, Emmanuel D.

doi:10.1002/anie.201806092

Cited by 44 publications

(52 citation statements)

References 197 publications

(248 reference statements)

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“…This is remarkable, because, during assembly, a growing complex has to discriminate its specific components from a multicomponent mixture of hundreds of different protein species that are part of the proteome. Failure to solve this discriminatory task could result in assembly of chimeric structures composed of fragments from different complexes, impairing normal cellular function (2).…”

mentioning

confidence: 99%

Lessons from equilibrium statistical physics regarding the assembly of protein complexes

Sartori

Leibler

2019

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

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Cellular functions are established through biological evolution, but are constrained by the laws of physics. For instance, the physics of protein folding limits the lengths of cellular polypeptide chains. Consequently, many cellular functions are carried out not by long, isolated proteins, but rather by multiprotein complexes. Protein complexes themselves do not escape physical constraints, one of the most important being the difficulty of assembling reliably in the presence of cellular noise. In order to lay the foundation for a theory of reliable protein complex assembly, we study here an equilibrium thermodynamic model of self-assembly that exhibits 4 distinct assembly behaviors: diluted protein solution, liquid mixture, "chimeric assembly," and "multifarious assembly." In the latter regime, different protein complexes can coexist without forming erroneous chimeric structures. We show that 2 conditions have to be fulfilled to attain this regime: 1) The composition of the complexes needs to be sufficiently heterogeneous, and 2) the use of the set of components by the complexes has to be sparse. Our analysis of publicly available databases of protein complexes indicates that cellular protein systems might have indeed evolved so as to satisfy both of these conditions. self-assembly | protein complex

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mentioning

confidence: 99%

Lessons from equilibrium statistical physics regarding the assembly of protein complexes

Sartori

Leibler

2019

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

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“…The cucurbit[8]uril probably stabilizes an intrinsic protein interaction by an increase of the local concentration due to the supramolecular binding of the appended FGG motifs. This facilitated dimerization is significantly different from engineering of the dimerization interface of proteins, which typically leads to a permanent change in dimerization affinity …”

Section: Discussionmentioning

confidence: 92%

“…Control over protein dimerization events is crucial for the study of protein function and the interplay between protein oligomerization state and activity . A variety of protein engineering and small‐molecule‐based approaches have been developed to induce or inhibit the dimerization of proteins in a controllable manner .…”

Section: Introductionmentioning

confidence: 99%

Cucurbit[8]uril Reactivation of an Inactivated Caspase‐8 Mutant Reveals Differentiated Enzymatic Substrate Processing

et al. 2018

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Caspase‐8 constructs featuring an N‐terminal FGG sequence allow for selective twofold recognition by cucurbit[8]uril, which leads to an increase of the enzymatic activity in a cucurbit[8]uril dose‐dependent manner. This supramolecular switching has enabled for the first time the study of the same caspase‐8 in its two extreme states; as full monomer and as cucurbit[8]uril induced dimer. A mutated, fully monomeric caspase‐8 (D384A), which is enzymatically inactive towards its natural substrate caspase‐3, could be fully reactivated upon addition of cucurbit[8]uril. In its monomeric state caspase‐8 (D384A) still processes a small synthetic substrate, but not the natural caspase‐3 substrate, highlighting the close interplay between protein dimerization and active site rearrangement for substrate selectivity. The ability to switch the caspase‐8 activity by a supramolecular system thus provides a flexible approach to studying the activity of a protein at different oligomerization states.

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“…The design of mesoscale synthetic protein assemblies is becoming increasingly powerful to create new materials [37][38][39] and functions [40][41][42] . Moreover, as we are only beginning to grasp the complexity of proteome self-organization, new approaches are needed for characterizing and understanding mesoscale properties of protein self-assembly in cells [43][44][45][46][47][48] .…”

Section: Discussionmentioning

confidence: 99%

Designer protein assemblies with tunable phase diagrams in living cells

Heidenreich

Georgeson

Locatelli

et al. 2020

Preprint

Self Cite

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The self-organization of proteins into specific assemblies is a hallmark of biological systems. Principles governing protein-protein interactions have long been known. However, principles by which such nanoscale interactions generate diverse phenotypes of mesoscale assemblies, including phase-separated compartments, remains challenging to characterize and understand. To illuminate such principles, we create a system of two proteins designed to interact and form mesh-like assemblies in living cells. We devise a novel strategy to map high-resolution phase diagrams in vivo , which provide mesoscale self-assembly signatures of our system. The structural modularity of the two protein components allows straightforward modification of their molecular properties, enabling us to characterize how point mutations that change their interaction affinity impact the phase diagram and material state of the assemblies in vivo . Both, the phase diagrams and their dependence on interaction affinity were captured by theory and simulations, including out-of-equilibrium effects seen in growing cells. Applying our system to interrogate biological mechanisms of self-assembly, we find that co-translational protein binding suffices to recruit an mRNA to the designed micron-scale structures.

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Infinite Assembly of Folded Proteins in Evolution, Disease, and Engineering

Cited by 44 publications

References 197 publications

Lessons from equilibrium statistical physics regarding the assembly of protein complexes

Lessons from equilibrium statistical physics regarding the assembly of protein complexes

Cucurbit[8]uril Reactivation of an Inactivated Caspase‐8 Mutant Reveals Differentiated Enzymatic Substrate Processing

Designer protein assemblies with tunable phase diagrams in living cells

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