Mechanical Transition from α-Helical Coiled Coils to β-Sheets in Fibrin(ogen)

Zhmurov, Artem; Kononova, Olga; Litvinov, Rustem I.; Dima, Ruxandra I.; Barsegov, Valeri; Weisel, John W.

doi:10.1021/ja3076428

Cited by 97 publications

(111 citation statements)

References 41 publications

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“…1 A) that consist of fibers (~100 nm diameter) that are themselves bundles of semiflexible protofibrils (~10 nm diameter). Fibrin gels are able to maintain their structural integrity and undergo reversible strain stiffening up to extraordinarily large strains of close to 300% (14), even though the constituent fibrils undergo changes in molecular structure at tensile strains above~40% (15). Here we demonstrate that structural adaptation at different length scales underlies fibrin's remarkable mechanical resilience.…”

Section: Introductionmentioning

confidence: 65%

“…There is already evidence of force-induced conformational changes (47) and unfolding of fibrin monomers (15) under mechanical loading, which may be responsible for the dissipative remodeling. Here, coarse-grained simulations are likely needed to connect molecular-scale insights from full-atom simulations to macroscale mechanics at the protofibril and fiber levels.…”

Section: Discussionmentioning

confidence: 99%

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Fibrin Networks Support Recurring Mechanical Loads by Adapting their Structure across Multiple Scales

Kurniawan

Vos

Biebricher

et al. 2016

Biophysical Journal

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Tissues and cells sustain recurring mechanical loads that span a wide range of loading amplitudes and timescales as a consequence of exposure to blood flow, muscle activity, and external impact. Both tissues and cells derive their mechanical strength from fibrous protein scaffolds, which typically have a complex hierarchical structure. In this study, we focus on a prototypical hierarchical biomaterial, fibrin, which is one of the most resilient naturally occurring biopolymers and forms the structural scaffold of blood clots. We show how fibrous networks composed of fibrin utilize irreversible changes in their hierarchical structure at different scales to maintain reversible stress stiffening up to large strains. To trace the origin of this paradoxical resilience, we systematically tuned the microstructural parameters of fibrin and used a combination of optical tweezers and fluorescence microscopy to measure the interactions of single fibrin fibers for the first time, to our knowledge. We demonstrate that fibrin networks adapt to moderate strains by remodeling at the network scale through the spontaneous formation of new bonds between fibers, whereas they adapt to high strains by plastic remodeling of the fibers themselves. This multiscale adaptation mechanism endows fibrin gels with the remarkable ability to sustain recurring loads due to shear flows and wound stretching. Our findings therefore reveal a microscopic mechanism by which tissues and cells can balance elastic nonlinearity and plasticity, and thus can provide microstructural insights into cell-driven remodeling of tissues.

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Section: Introductionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Fibrin Networks Support Recurring Mechanical Loads by Adapting their Structure across Multiple Scales

Kurniawan

Vos

Biebricher

et al. 2016

Biophysical Journal

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“…A mechanical force-induced α-to-β transition has been observed in fibrin (22), collagen, and vimentin (26). The simulations in the works by Qin et al (26) and Zhmurov et al (22) on the α-to-β transition in the coiled coils of fibrin and vimentin indicate that mechanical force directly drives the transition. Their simulations also show that a β-seeded region should transform first in harmony with our results for CPEB-Q.…”

Section: α-Helix To β-Sheet Transition In a Coiled Coil Is Promoted Bmentioning

confidence: 92%

“…This observation suggests that an external driving force will be needed in vivo. The α-helix to β-sheet (α-to-β) transition in other coiled coils has been shown to be enhanced by mechanical force (21,22), high temperature (23), pH change (24), and high protein concentration (25). A mechanical force-induced α-to-β transition has been observed in fibrin (22), collagen, and vimentin (26).…”

Section: α-Helix To β-Sheet Transition In a Coiled Coil Is Promoted Bmentioning

confidence: 99%

“…The α-helix to β-sheet (α-to-β) transition in other coiled coils has been shown to be enhanced by mechanical force (21,22), high temperature (23), pH change (24), and high protein concentration (25). A mechanical force-induced α-to-β transition has been observed in fibrin (22), collagen, and vimentin (26). The simulations in the works by Qin et al (26) and Zhmurov et al (22) on the α-to-β transition in the coiled coils of fibrin and vimentin indicate that mechanical force directly drives the transition.…”

Section: α-Helix To β-Sheet Transition In a Coiled Coil Is Promoted Bmentioning

confidence: 99%

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Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory

Chen

Zheng

Wolynes

2016

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

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Aplysia cytoplasmic polyadenylation element binding (CPEB) protein, a translational regulator that recruits mRNAs and facilitates translation, has been shown to be a key component in the formation of long-term memory. Experimental data show that CPEB exists in at least a low-molecular weight coiled-coil oligomeric form and an amyloid fiber form involving the Q-rich domain (CPEB-Q). Using a coarse-grained energy landscape model, we predict the structures of the low-molecular weight oligomeric form and the dynamics of their transitions to the β-form. Up to the decamer, the oligomeric structures are predicted to be coiled coils. Free energy profiles confirm that the coiled coil is the most stable form for dimers and trimers. The structural transition from α to β is shown to be concentration dependent, with the transition barrier decreasing with increased concentration. We observe that a mechanical pulling force can facilitate the α-helix to β-sheet (α-to-β) transition by lowering the free energy barrier between the two forms. Interactome analysis of the CPEB protein suggests that its interactions with the cytoskeleton could provide the necessary mechanical force. We propose that, by exerting mechanical forces on CPEB oligomers, an active cytoskeleton can facilitate fiber formation. This mechanical catalysis makes possible a positive feedback loop that would help localize the formation of CPEB fibers to active synapse areas and mark those synapses for forming a long-term memory after the prion form is established. The functional role of the CPEB helical oligomers in this mechanism carries with it implications for targeting such species in neurodegenerative diseases.long-term memory | mechanical prion | protein aggregation | Q-rich protein I t is widely believed that learning involves the modification in number, strength, and structure of specific localized synaptic connections. Although short-term memory formation occurs without protein synthesis, establishing long-term memory (LTM) involves protein synthesis localized at the synapse area, thus requiring a stable translational regulatory system that activates mRNA and protein synthesis in the synapse (1-3). It has long been recognized that the relatively short half-life of most proteins in eukaryotic cells (4) poses questions about the long timescales over which memories can be retained. It has been suggested that forming a very stable prion could provide a mechanism for achieving memory longevity (5, 6). An excellent candidate species has emerged from the works of Kandel and coworkers (1-3) and Lindquist and coworker (6) on cytoplasmic polyadenylation element binding (CPEB). It has been established, in Aplysia, that Aplysia cytoplasmic polyadenylation element binding (ApCPEB) activates mRNA and mediates synaptic protein synthesis for at least 72 h and that it does so by taking on a functional prion-like form (3, 7). Forming the prion is, thus, a key element in LTM formation and maintenance.Prions were first proposed as protein-only infectious particles causing Creu...

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Scaffold, mechanics and functions of nuclear lamins

Buxboim,

Kronenberg‐Tenga,

Salajkova

et al. 2023

FEBS Letters

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Nuclear lamins are type‐V intermediate filaments that are involved in many nuclear processes. In mammals, A‐ and B‐type lamins assemble into separate physical meshwork underneath the inner nuclear membrane, the nuclear lamina, with some residual fraction localized within the nucleoplasm. Lamins are the major part of the nucleoskeleton, providing mechanical strength and flexibility to protect the genome and allow nuclear deformability, while also contributing to gene regulation via interactions with chromatin. While lamins are the evolutionary ancestors of all intermediate filament family proteins, their ultimate filamentous assembly is markedly different from their cytoplasmic counterparts. Interestingly, hundreds of genetic mutations in the lamina proteins have been causally linked with a broad range of human pathologies, termed laminopathies. These include muscular, neurological and metabolic disorders, as well as premature aging diseases. Recent technological advances have contributed to resolving the filamentous structure of lamins and the corresponding lamina organization. In this review, we revisit the multiscale lamin organization and discuss its implications on nuclear mechanics and chromatin organization within lamina‐associated domains.

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Mechanical Transition from α-Helical Coiled Coils to β-Sheets in Fibrin(ogen)

Cited by 97 publications

References 41 publications

Fibrin Networks Support Recurring Mechanical Loads by Adapting their Structure across Multiple Scales

Fibrin Networks Support Recurring Mechanical Loads by Adapting their Structure across Multiple Scales

Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory

Scaffold, mechanics and functions of nuclear lamins

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