Dynamins and BAR Proteins-Safeguards against Cancer

Sundborger, Anna; Hinshaw, Jenny E.

doi:10.1615/critrevoncog.v20.i5-6.160

Cited by 2 publications

(2 citation statements)

References 93 publications

(117 reference statements)

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“…Dynamin family members are mechanochemical GTPases that catalyze membrane remodeling during essential cellular processes 1 . Mutations in dynamins are associated with neuropathies 4 and atypical expression levels of dynamins are associated with diverse cancers 5 while several viruses (e.g. HIV) hijack dynamin-dependent pathways 6,7 .…”

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confidence: 99%

Cryo-EM of the dynamin polymer assembled on lipid membrane

Kong

Sochacki

Wang

et al. 2018

Nature

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144

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Membrane fission is a fundamental process in the regulation and remodelling of cell membranes. Dynamin, a large GTPase, mediates membrane fission by assembling around, constricting and cleaving the necks of budding vesicles. Here we report a 3.75 Å resolution cryo-electron microscopy structure of the membrane-associated helical polymer of human dynamin-1 in the GMPPCP-bound state. The structure defines the helical symmetry of the dynamin polymer and the positions of its oligomeric interfaces, which were validated by cell-based endocytosis assays. Compared to the lipid-free tetramer form, membrane-associated dynamin binds to the lipid bilayer with its pleckstrin homology domain (PHD) and self-assembles across the helical rungs via its guanine nucleotide-binding (GTPase) domain. Notably, interaction with the membrane and helical assembly are accommodated by a severely bent bundle signalling element (BSE), which connects the GTPase domain to the rest of the protein. The BSE conformation is asymmetric across the inter-rung GTPase interface, and is unique compared to all known nucleotide-bound states of dynamin. The structure suggests that the BSE bends as a result of forces generated from the GTPase dimer interaction that are transferred across the stalk to the PHD and lipid membrane. Mutations that disrupted the BSE kink impaired endocytosis. We also report a 10.1 Å resolution cryo-electron microscopy map of a super-constricted dynamin polymer showing localized conformational changes at the BSE and GTPase domains, induced by GTP hydrolysis, that drive membrane constriction. Together, our results provide a structural basis for the mechanism of action of dynamin on the lipid membrane.

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confidence: 99%

Cryo-EM of the dynamin polymer assembled on lipid membrane

Kong

Sochacki

Wang

et al. 2018

Nature

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144

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“…Here, we explored the short-term mechanotransduction events involved. Interestingly, several of the molecular players discussed (BAR proteins [170][171][172], TORC2 [173], MGCs [174] Arf1 [175,176] and caveolae [177,178]) are involved in different cancer scenarios, potentially through altered mechanical responses. However, how this occurs, and how it is linked to long-term cellular response to mechanical signals, remains as an open question and is likely to be an exciting area of research.…”

Section: Discussionmentioning

confidence: 99%

The plasma membrane as a mechanochemical transducer

Roux

Quiroga

Walani

et al. 2019

Phil. Trans. R. Soc. B

155

118

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Cells are constantly submitted to external mechanical stresses, which they must withstand and respond to. By forming a physical boundary between cells and their environment that is also a biochemical platform, the plasma membrane (PM) is a key interface mediating both cellular response to mechanical stimuli, and subsequent biochemical responses. Here, we review the role of the PM as a mechanosensing structure. We first analyse how the PM responds to mechanical stresses, and then discuss how this mechanical response triggers downstream biochemical responses. The molecular players involved in PM mechanochemical transduction include sensors of membrane unfolding, membrane tension, membrane curvature or membrane domain rearrangement. These sensors trigger signalling cascades fundamental both in healthy scenarios and in diseases such as cancer, which cells harness to maintain integrity, keep or restore homeostasis and adapt to their external environment. This article is part of a discussion meeting issue ‘Forces in cancer: interdisciplinary approaches in tumour mechanobiology’.

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Dynamins and BAR Proteins-Safeguards against Cancer

Cited by 2 publications

References 93 publications

Cryo-EM of the dynamin polymer assembled on lipid membrane

Cryo-EM of the dynamin polymer assembled on lipid membrane

The plasma membrane as a mechanochemical transducer

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