Ambidextrous helical nanotubes from self-assembly of designed helical hairpin motifs

Hughes, Spencer; Wang, Fengbin; Wang, Shengyuan; Kreutzberger, Mark A.; Osinski, T.; Orlova, Albina; Wall, Joseph S.; Zuo, Xiaobing; Conticello, Vincent P.

doi:10.1073/pnas.1903910116

Cited by 33 publications

(34 citation statements)

References 76 publications

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“…Supercoiling of filaments was only observed under conditions in which the cross-α orientation was not maintained in the extended structure. In addition, our cross-α nanotubes differed from classical coiled-coils, in that the helical packing in a protofilament displayed an open or extended mode of association that is reminiscent of solenoidal tandem repeat proteins 10 , 11 , 76 , 77 . Most coiled-coils form closed assemblies of defined oligomerization state, which are often, but not exclusively, based on cyclic symmetry in which the helical protomers are aligned nearly parallel to the super-helical axis 78 , 79 .…”

Section: Discussionmentioning

confidence: 84%

Structural analysis of cross α-helical nanotubes provides insight into the designability of filamentous peptide nanomaterials

et al. 2021

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The exquisite structure-function correlations observed in filamentous protein assemblies provide a paradigm for the design of synthetic peptide-based nanomaterials. However, the plasticity of quaternary structure in sequence-space and the lability of helical symmetry present significant challenges to the de novo design and structural analysis of such filaments. Here, we describe a rational approach to design self-assembling peptide nanotubes based on controlling lateral interactions between protofilaments having an unusual cross-α supramolecular architecture. Near-atomic resolution cryo-EM structural analysis of seven designed nanotubes provides insight into the designability of interfaces within these synthetic peptide assemblies and identifies a non-native structural interaction based on a pair of arginine residues. This arginine clasp motif can robustly mediate cohesive interactions between protofilaments within the cross-α nanotubes. The structure of the resultant assemblies can be controlled through the sequence and length of the peptide subunits, which generates synthetic peptide filaments of similar dimensions to flagella and pili.

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Section: Discussionmentioning

confidence: 84%

Structural analysis of cross α-helical nanotubes provides insight into the designability of filamentous peptide nanomaterials

et al. 2021

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“…To conclude, the atomic structures of human and primate antibacterial LL-37 17-29 showed a functional supramolecular nanostructure of densely packed amphipathic helices. This assembly into stable fibrils with a surface forming hydrophobic/charged zigzagged belts can be used as scaffolds for wide-ranging applications in bio and nanotechnology, regenerative medicine and bioengineering 53 , with the invaluable advantage of an inherent antibacterial activity. Links between fibril formation and antimicrobial activity are accumulating [11][12][13][14][17][18][19][20][21]54 , and here, we fibrils, such as collagen, actin, and fibrinogen.…”

Section: Discussionmentioning

confidence: 99%

The Human LL-37(17-29) antimicrobial peptide reveals a functional supramolecular structure

2020

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Here, we demonstrate the self-assembly of the antimicrobial human LL-37 active core (residues 17-29) into a protein fibril of densely packed helices. The surface of the fibril encompasses alternating hydrophobic and positively charged zigzagged belts, which likely underlie interactions with and subsequent disruption of negatively charged lipid bilayers, such as bacterial membranes. LL-37 17-29 correspondingly forms wide, ribbon-like, thermostable fibrils in solution, which co-localize with bacterial cells. Structure-guided mutagenesis analyses supports the role of self-assembly in antibacterial activity. LL-37 17-29 resembles, in sequence and in the ability to form amphipathic helical fibrils, the bacterial cytotoxic PSMα3 peptide that assembles into cross-α amyloid fibrils. This argues helical, self-assembling, basic building blocks across kingdoms of life and points to potential structural mimicry mechanisms. The findings expose a protein fibril which performs a biological activity, and offer a scaffold for functional and durable biomaterials for a wide range of medical and technological applications.

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“…14 c ). Cryo-EM structures at near-atomic resolution demonstrated the formation of tubes with outer radii of 70 or 80 Å (Hughes et al ., 2019).…”

Section: Design Of Protein Assembliesmentioning

confidence: 99%

De novoprotein design, a retrospective

Korendovych

DeGrado

2020

Quart. Rev. Biophys.

188

179

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Proteins are molecular machines whose function depends on their ability to achieve complex folds with precisely defined structural and dynamic properties. The rational design of proteins from first-principles, or de novo, was once considered to be impossible, but today proteins with a variety of folds and functions have been realized. We review the evolution of the field from its earliest days, placing particular emphasis on how this endeavor has illuminated our understanding of the principles underlying the folding and function of natural proteins, and is informing the design of macromolecules with unprecedented structures and properties. An initial set of milestones in de novo protein design focused on the construction of sequences that folded in water and membranes to adopt folded conformations. The first proteins were designed from first-principles using very simple physical models. As computers became more powerful, the use of the rotamer approximation allowed one to discover amino acid sequences that stabilize the desired fold. As the crystallographic database of protein structures expanded in subsequent years, it became possible to construct proteins by assembling short backbone fragments that frequently recur in Nature. The second set of milestones in de novo design involves the discovery of complex functions. Proteins have been designed to bind a variety of metals, porphyrins, and other cofactors. The design of proteins that catalyze hydrolysis and oxygen-dependent reactions has progressed significantly. However, de novo design of catalysts for energetically demanding reactions, or even proteins that bind with high affinity and specificity to highly functionalized complex polar molecules remains an importnant challenge that is now being achieved. Finally, the protein design contributed significantly to our understanding of membrane protein folding and transport of ions across membranes. The area of membrane protein design, or more generally of biomimetic polymers that function in mixed or non-aqueous environments, is now becoming increasingly possible.

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Ambidextrous helical nanotubes from self-assembly of designed helical hairpin motifs

Cited by 33 publications

References 76 publications

Structural analysis of cross α-helical nanotubes provides insight into the designability of filamentous peptide nanomaterials

Structural analysis of cross α-helical nanotubes provides insight into the designability of filamentous peptide nanomaterials

The Human LL-37(17-29) antimicrobial peptide reveals a functional supramolecular structure

De novoprotein design, a retrospective

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