Biochemical and mechanical regulation of actin dynamics

Lappalainen, Pekka; Kotila, Tommi; Jégou, Antoine; Romet-Lemonne, Guillaume

doi:10.1038/s41580-022-00508-4

Cited by 156 publications

(113 citation statements)

References 217 publications

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“…This energy-dependent process can be observed at several hierarchical levels, where the stability of a biological component is supported by the turnover of its building blocks (Rafelski & Marshall, 2008; Chan & Marshall, 2012; Goehring & Hyman, 2012). In eukaryotes, the actin cytoskeleton plays many key roles in maintaining dynamic intracellular organization (Chhabra & Higgs, 2007; Lappalainen et al , 2022). For example, actin dynamics in the cortex (Fritzsche et al , 2013, 2016), lamellipodium (Pollard & Borisy, 2003) or stress fibers (Hotulainen & Lappalainen, 2006; Tojkander et al , 2015; Nishimura et al , 2021) underpin cell migration (Lai et al , 2008; Burnette et al , 2011; Rottner & Stradal, 2011; Blanchoin et al , 2014), and organelle dynamics (Chakrabarti et al , 2021).…”

Section: Introductionmentioning

confidence: 99%

Recycling limits the lifetime of actin turnover

Blanchoin

Théry

Colin

et al. 2022

Preprint

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Intracellular organization is largely mediated by the actin turnover. Cellular actin networks consume matter and energy to sustain their dynamics, while maintaining their appearance. This behavior, called 'dynamic steady state', enables cells to sense and adapt to their environment. However, how structural stability can be maintained during the constant turnover of a limited actin monomer pool is poorly understood. To answer this question, we developed an experimental system using actin bead motility in a cell-sized compartment with a limited amount of monomer. We used the speed and the size of the actin comet tails to evaluate the system's monomer consumption and its lifetime. We established the relative contribution of actin assembly, disassembly and recycling for a bead movement over tens of hours. Recycling mediated by cyclase-associated proteins is the key step in allowing the reuse of monomers for multiple assembly cycles. Energy supply and protein aging are also factors that limit the lifetime of actin turnover. This work reveals the balancing mechanism for long-term network assembly with a limited amount of building blocks.

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Section: Introductionmentioning

confidence: 99%

Recycling limits the lifetime of actin turnover

Blanchoin

Théry

Colin

et al. 2022

Preprint

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“…In the cytosol, where the actin concentration is far beyond the critical concentration for polymerization, cooperative behaviors of regulatory proteins accelerate the spontaneous tread-milling and/or facilitate filament turnover by promoting multiple reactions involving nucleation, capping, and severing, to drive fast cell migration ( 12 , 13 ). Recent progress, particularly in kinetic analyses of single actin filaments, has revealed the contribution of the barbed end disassembly to monomer recycling ( 14 , 15 ). Pi release dramatically alters the assembly properties of actin filaments in two ways: 1) by promoting spontaneous depolymerization and, more importantly, 2) by making the ADP-actin subunits more attractive to proteins that facilitate filament disassembly such as ADF/cofilin.…”

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confidence: 99%

Structures and mechanisms of actin ATP hydrolysis

Kanematsu

Narita

Oda

et al. 2022

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

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The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell motility. This mechanical work is driven by the ATPase activity at the catalytic site in the F-form. For deeper understanding of the actin cellular functions, the reaction mechanism must be elucidated. Here, we show that a single actin molecule is trapped in the F-form by fragmin domain-1 binding and present their crystal structures in the ATP analog-, ADP-Pi-, and ADP-bound forms, at 1.15-Å resolutions. The G-to-F conformational transition shifts the side chains of Gln137 and His161, which relocate four water molecules including W1 (attacking water) and W2 (helping water) to facilitate the hydrolysis. By applying quantum mechanics/molecular mechanics calculations to the structures, we have revealed a consistent and comprehensive reaction path of ATP hydrolysis by the F-form actin. The reaction path consists of four steps: 1) W1 and W2 rotations; 2) P G –O 3B bond cleavage; 3) four concomitant events: W1–PO 3 − formation, OH − and proton cleavage, nucleophilic attack by the OH − against P G , and the abstracted proton transfer; and 4) proton relocation that stabilizes the ADP-Pi–bound F-form actin. The mechanism explains the slow rate of ATP hydrolysis by actin and the irreversibility of the hydrolysis reaction. While the catalytic strategy of actin ATP hydrolysis is essentially the same as those of motor proteins like myosin, the process after the hydrolysis is distinct and discussed in terms of Pi release, F-form destabilization, and global conformational changes.

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“…Finally, the recruited actins must be physically oriented in a manner that is sufficient to stabilize small oligomers (dimers, trimers, or tetramers), in order to facilitate the addition of further actin subunits [ 23 , 24 , 25 , 26 ]. Here, oligomerization is known to play an important role, as seen for eukaryotic actin assembly factors: formins dimerize via their FH2 domains, Ena/VASP tetramerizes through a C-terminal coiled-coil motif, and tandem monomer-binding nucleators dimerize indirectly, by associating with dimeric proteins, for efficient actin assembly [ 24 ].…”

Section: Lessons Learnedmentioning

confidence: 99%

“…The study of pathogen effectors, their interactions with the infected host cell macromolecules, and their impact on host cell biology, has generally yielded major insights into both the biology of the pathogen and the infected host [ 107 , 108 ]. This review focuses on the insights gained from the study of a class of pathogen effectors that directly assemble actin filaments on our general understanding of the basic principles of actin assembly at a structural and molecular level, which has been [ 23 , 24 ], and continues to be [ 25 , 26 ], of immense interest. These effectors display some similarities with eukaryotic actin assembly factors, but, as discussed earlier, they have evolved novel mechanisms.…”

Section: Outlook and Perspectivementioning

confidence: 99%

“…Cellular control of actin assembly has and continues to be the subject of intense research interest given how central actin is to essential cellular processes [ 19 , 20 , 21 , 22 ]. Molecular dissection of their mechanism of actin assembly offers an opportunity to gain significant insights into fundamental determinants for actin assembly [ 23 , 24 , 25 , 26 ]. Finally, their study would inform our understanding of host–pathogen interactions, pathogenicity mechanisms in general, and offer the potential of targeting their respective disease-causing pathogen with therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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Functional Mimicry of Eukaryotic Actin Assembly by Pathogen Effector Proteins

Alqassim

2022

IJMS

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The actin cytoskeleton lies at the heart of many essential cellular processes. There are hundreds of proteins that cells use to control the size and shape of actin cytoskeletal networks. As such, various pathogens utilize different strategies to hijack the infected eukaryotic host actin dynamics for their benefit. These include the control of upstream signaling pathways that lead to actin assembly, control of eukaryotic actin assembly factors, encoding toxins that distort regular actin dynamics, or by encoding effectors that directly interact with and assemble actin filaments. The latter class of effectors is unique in that, quite often, they assemble actin in a straightforward manner using novel sequences, folds, and molecular mechanisms. The study of these mechanisms promises to provide major insights into the fundamental determinants of actin assembly, as well as a deeper understanding of host–pathogen interactions in general, and contribute to therapeutic development efforts targeting their respective pathogens. This review discusses mechanisms and highlights shared and unique features of actin assembly by pathogen effectors that directly bind and assemble actin, focusing on eukaryotic actin nucleator functional mimics Rickettsia Sca2 (formin mimic), Burkholderia BimA (Ena/VASP mimic), and Vibrio VopL (tandem WH2-motif mimic).

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Biochemical and mechanical regulation of actin dynamics

Cited by 156 publications

References 217 publications

Recycling limits the lifetime of actin turnover

Recycling limits the lifetime of actin turnover

Structures and mechanisms of actin ATP hydrolysis

Functional Mimicry of Eukaryotic Actin Assembly by Pathogen Effector Proteins

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