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ScienceDirect
Interplay between membrane curvature and the actin
cytoskeleton
Michael M. Kessels and Britta Qualmann
Abstract
An intimate interplay of the plasma membrane with curvaturesensing and curvature-inducing proteins would allow for
defining specific sites or nanodomains of action at the plasma
membrane, for example, for protrusion, invagination, and polarization. In addition, such connections are predestined to
ensure spatial and temporal order and sequences. The combined forces of membrane shapers and the cortical actin
cytoskeleton might hereby in particular be required to overcome the strong resistance against membrane rearrangements in case of high plasma membrane tension or cellular
turgor. Interestingly, also the opposite might be necessary, the
inhibition of both membrane shapers and cytoskeletal reinforcement structures to relieve membrane tension to protect
cells from membrane damage and rupturing during mechanical
stress. In this review article, we discuss recent conceptual
advances enlightening the interplay of plasma membrane
curvature and the cortical actin cytoskeleton during endocytosis, modulations of membrane tensions, and the shaping of
entire cells.
Addresses
Institute of Biochemistry I, Jena University Hospital, Friedrich Schiller
University Jena, Nonnenplan 2-4, 07743, Jena, Germany
Corresponding author: Qualmann, Britta (Britta.Qualmann@med.unijena.de)
Current Opinion in Cell Biology 2021, 68:10–19
This review comes from a themed issue on Cell Architecture
Edited by Pekka Lappalainen and Pierre Coulombe
For a complete overview see the Issue and the Editorial
https://doi.org/10.1016/j.ceb.2020.08.008
0955-0674/© 2020 Elsevier Ltd. All rights reserved.
Introduction
Cellular membranes represent natural barriers and
thereby bring about the required compartmentalization
of life functions. Curving biological membranes establishes the complex and distinct membrane architectures
of individual cells and mediates membrane traffic to
ensure cross talk and material exchange among the
different compartments and with the extracellular
space. Sculpturing plasma membrane protrusions, such
Current Opinion in Cell Biology 2021, 68:10–19
as microvilli and cilia, represents a mean to increase the
cell surface area allowing for increased resorption,
excretion, and/or signaling, whereas sculpturing inward,
folds and tubules provide reservoirs to relieve membrane tensions or increase vesicular uptake. Modulations
of membrane topologies furthermore give rise to segregated cellular subcompartments and establish microdomains for spatially defined assemblies of cellular
machineries.
Because pure lipid bilayers remain flat [1], energy is
required to invaginate, protrude, bend, fuse, or break
membranes against the odds of membrane resistance.
Structural membrane inhomogeneities are brought
about by mechanisms of direct membrane bending
within the lipid bilayer, such as lipid composition
asymmetry, intrinsic shape of membrane-spanning segments or asymmetric insertion of protein domains
(hairpins, wedges, and so on). In addition, peripheral
exertion of forces can induce curvatures via inherently
curved peripheral binding proteins or via pulling or
pushing forces by cytoskeletal elements [2e4].
Very prominent among membrane shapers is the superfamily of BineAmphiphysineRvs (BAR) domain
proteins. Extensive structural work on BAR domains has
revealed a common structural element that can serve as
an extended crescent-shaped membrane-binding interface and has allowed the grouping of the BAR domain
superfamily into subfamilies with structurally slightly
distinct BAR domain subtypes (N-BAR, BAR, F-BAR,
and I-BAR) according to the degree and direction
(convex/concave) of curvature adopted. BAR domain
superfamily proteins are thought to recognize suitably
curved membrane topologies and/or to actively bend
membranes into curved topologies. In some of the BAR
domain proteins, this scaffolding mechanism is combined with a second general mechanism of membrane
bending, the insertion of hydrophobic protein folds into
only one leaflet of the membrane, which will lead to an
outward curvature induction [3,5e9]. However, the
working model that solely the intrinsic curvature of BAR
domains would determine their functions is highly
oversimplified. First, membrane association mechanisms
exhibit increased versatility through diagonal placing,
lateral lipid-binding modes, additional lipid-binding
modules, tilde shapes, and formation of macromolecular
lattices with different modes of organization and
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Membrane curvature and actin cytoskeleton Kessels and Qualmann
arrangement. Second, additional proteineprotein
interaction modules in a large variety of BAR domain
proteins allow them to additionally recruit and connect
different binding partners and ensure the connection
and coordination of different events in time and space
11
and may thereby offer mechanistic explanations for how
coordination, directionality, and effectiveness of complex processes with several steps and key players can be
achieved. Although the reports on direct binding of BAR
domains to actin [10e12] still lack confirmation of
Figure 1
Interplay of actin filament formation and membrane curvature at endocytic sites in metazoan cells. (a) A prototype of endocytic vesicle formation is
occurring at clathrin-coated pits. BAR domain proteins with their differently curved membrane-binding interfaces (depicted are FCHSDs, FCHO, FBP17,
syndapins, and endophilins) sense and promote increasing membrane curvature at invaginating sites via spatiotemporal and sequential membrane
association and also accommodate more complex membrane topologies by additionally offering tilde-shaped membrane interfaces (FCHO, syndapins).
(b) Importantly, especially several proteins of the F-BAR subfamily additionally associate with N-WASP and — together with local PIP2 signals in the
endocytic membrane (not depicted) — lead to recruitment and activation of the Arp2/3 complex activator N-WASP and thereby to locally defined actin
nucleation. (c) These newly formed actin filaments support the vesicle formation process by force generation. These forces are transmitted by Factin–binding tethering components, which link newly formed and elongating actin filaments to the endocytic coat, the dynamin-driven endocytic fission
machinery and/or the plasma membrane surrounding the coated pit.
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Current Opinion in Cell Biology 2021, 68:10–19
12 Cell Architecture
functional significance [8], there are striking molecular
and functional links between BAR domainecontaining
proteins and actin filament assembly machineries
[7,8,13].
In this review, we will highlight and discuss recent reports (mainly over the last two years) that provided
important conceptually new insights into the connection of plasma membrane curvature and the cortical
actin cytoskeleton during endocytosis, modulations of
membrane tensions, and during the shaping of entire
cells. Hereby, special emphasis will be laid on the
following questions:
Why is an interplay and a coordination of membrane
curvature and the cytoskeleton so important? One
could argue that pulling and pushing forces of actin
filament assembly or elongation and/or the action of
motor proteins would be sufficient for curvature
induction.
How is such an interplay brought about at the molecular level? Here, we will cover curvature-sensing
proteins, mainly BAR domainecontaining proteins,
that additionally regulate cortical cytoskeletal effectors in time and space.
What is cause and what is consequence d several
hen-and-egg questions:
How is the initial curvature generated? What are
the relative contributions of curvature sensing
versus curvature generation? How does curvature
affect recruitment and interaction of membrane
shapers and cytoskeletal elements? Or is
recruitment rather occurring via certain signals,
such as local Ca2þ influx, local alterations in
membrane tension, or membrane lipid distribution or via interaction with other cells or the
substratum?
Is the function of the cytoskeleton rather to induce
curvature d by actin polymerization forces or actin/
myosin motor activity? Or is there primarily a
curvature-sensitive regulation of cytoskeletal forces
or organization? Or is its major function to stabilize
existing curvatures?
The tug of war between membrane tension
and curvature induction – does the
cytoskeleton tip the scales?
Endocytic internalization requires extensive membrane
curvature changes (Figure 1) involving membrane curvature generation or stabilization by membrane shapers,
such as BAR domain proteins, as well as a local decrease
in turgor pressure, spatially defined and restricted actin
polymerization forces, and/or myosin motor activity
[2,14e17]. The requirements for mechanical forces
provided by cytoskeletal elements for endocytosis
apparently vary depending on membrane tension. This
may explain the strict dependence on Arp2/3 complexe
Current Opinion in Cell Biology 2021, 68:10–19
mediated actin network formation in yeast, which
exhibit high turgor pressure, but not in metazoan cells
[18].
Recent studies have provided new insights into this
intimate interplay between membrane curvature and
actin polymerization forces in clathrin-mediated endocytosis (Figure 1 and Figure 2). Particularly the use of
live-imaging methods and superresolution microscopyd
especially informative when combined with electron
microscopy to truly reveal membrane curvature d
allowed for visualizing the spatiotemporal order of
events, for quantifying involved machinery and for
comparisons with theoretical calculations.
A definite identification of membrane curvature at the
nanometer range ultimately requires the application of
electron microscopical methods. By combining again live
imaging with correlative microscopy [19,20], the analysis of mutants of budding yeast actin network components highlighted that actin polymerization and the
presence of membrane-binding coat proteins were
individually not sufficient to induce stable membrane
curvature, if they were not coupled to each other.
Similarly, actin filament cross-linking was required for
initiation of membrane bending and reaching scission
stage [21]. The authors propose that the expanding
actin network drives plasma membrane invagination in
different stages (Figure 2a).
A recent revisit of quantitative models of force production during clathrin-mediated endocytosis by singlemolecule lifetime measurements suggested that actin,
actin-associated proteins, and membrane-associated
proteins in fission yeast endocytic patches turned over
5 times or more during the formation of an endocytic
vesicle [22]. Interestingly, the geometry of actin filament formation during this process appears to be tightly
regulated. In budding yeast, single-molecule localization
microscopy revealed that endocytic proteins assemble
according to their function in a radially organized
manner. WASP family proteins form a ring-shaped
nanoscale template on flat membranes d most likely
because the core coat proteins form a tight and densely
packed lattice that prevents late arrivers from entering
the center of an endocytic side d to spatially control
actin filament nucleation. This geometry is expected to
provide sufficient pulling force for membrane invagination even in yeast with its high turgor pressure [23].
A different molecular mechanism for allowing a control
of the geometry of actin polymerization in form of an
annulus at rather flat areas surrounding the area of
coated pit initiation for invagination progression has
been suggested for the F-BAR domain protein FCHSD2
due to the rather flat geometry of its F-BAR domain
[24]. Intriguingly, the involvement of BAR domain
superfamily proteins in endocytosis seems thus not
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Membrane curvature and actin cytoskeleton Kessels and Qualmann
13
Figure 2
Mechanisms of force generation upon endocytic membrane invagination by actin filaments. Currently proposed mechanisms, by which actin filaments
support the endocytic vesicle formation process by local force generation, include: (a) actin filament formation and elongation creating massive pushing
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Current Opinion in Cell Biology 2021, 68:10–19
14 Cell Architecture
restricted to their ability to recognize, stabilize, and
induce curved membrane topologies, but the linkage of
actin polymerization to flat plasma membrane areas at
certain stages of the endocytic process appears similarly
important. BAR domains with their rather large,
extended membrane-binding interface are suitable for
detecting and distinguishing truly flat membrane areas.
Combining multiscale modeling of plasma membrane
mechanics and actin filament dynamics with live-cell
molecule counting and cryoelectron tomography in
human cells in a very recent study described that a
minimal branched actin network is sufficient for the
progression of endocytic pits against physiological
membrane tension [25]. Importantly, elastic energy
stored in the bending of longer actin filaments between
the two attachment sites at the coat and the base of the
endocytic pit (Figure 2b) might provide force for
endocytosis progression even when polymerization is
stalled due to capping. This makes endocytosis adaptable and somewhat resilient [25].
Recent studies on the role of actin motor proteins of the
myosin family in clathrin-mediated endocytosis suggest
further molecular mechanisms. One recent study
favored a model where budding yeast type I myosin d
independent of its motor activity [26] d and particularly its membrane recruitment are important for
restricting Arp2/3 complexemediated actin polymerization to and at endocytic sites generating force in a
defined direction for invagination progression [27].
Another working model proposed that yeast type I
myosin reorients or translocates actin filaments, thereby
relieving physical barbed (plus) end blockages by the
plasma membrane and promoting actin filament elongation providing force for progression of membrane
internalization. This promotion of the expansion of the
actin network was independent of the actin nucleation
promoting activity of yeast type I myosins [28]
(Figure 2c).
Minus-end (pointed end)edirected motor proteins
might be particularly important to win the tug of war for
efficient, sustained membrane bending against high
membrane tension [29-31,32]. The long isoform of
myosin VI might play a double role in the spatiotemperal
organization of membrane bending and cytoskeletal
forces. First, by competing with actin-binding clathrincoated pit components for direct binding of a clathrin
light chain, later by acting as a processive cellular motor
on branched actin for inward movement, and potentially
even fission [32]. Some recent studies might indicate
that even the myosin VI lipid interaction has some
curvature sensitivity on its own and might contribute to
remodel membrane geometry independent of its motor
domain activity [33].
Relieving membrane bending as a
protective measure to counteract
membrane tension and mechanical stress
Local changes in curvature of plasma membrane domains d particularly caveolae d play an important role
in preventing membrane rupture. Caveolae have the
ability to flatten out in response to osmotic swelling and
mechanical stretching reducing plasma membrane tension, thereby protecting cells exposed to mechanical
stress [34e36]. Interestingly, particularly membrane
curvature-sensing and curvature-shaping proteins of the
F-BAR domainecontaining protein family have d in
addition to the classical caveolar coat components,
caveolins and cavins d been reported to play a major
role in generating such plasma membrane reservoirs
[37]. Knockout of the F-BAR domain protein syndapin
III rendered cells vulnerable to increased membrane
tensions. Skeletal muscles of syndapin III knockout
mice showed pathological defects upon physical exercise reminiscent of the clinical symptoms of human
myopathies in line with syndapin III’s crucial role in
forming a membrane buffer reservoir represented by
invaginated caveolae [38].
Recognition and transduction of membrane tension to
changes in membrane bending and cytoskeletal organization in caveolar organization furthermore involves a
mechanosensing and mechanoadaptation system
composed of the tyrosine kinase c-Abl that transduces
forces, (b) the release of energy stored in bent filaments, and (c) a myosin-assisted increase of barbed end accessibility at membrane interfaces. All three
mechanisms are depicted in two temporal stages (upper, earlier stage; lower; later stage) to visualize the changes leading to force generation (forces are
depicted as thick blue arrows). According to calculations — at least in yeast and under high pressure — such forces by actin polymerization are, however,
not sufficient. Further mechanisms are thus required and might include myosin motor activity, membrane curvature generation or stabilization by
membrane shapers, or local decrease in turgor pressure [18]. In (a), gaps between barbed (plus) ends of actin filaments facing the plasma membrane
open via rapid thermal fluctuations and allow for actin monomer addition and filament elongation in a Brownian ratchet-type mechanism (orange, previously formed stretches of F-actin; dark red, newly added during the elongation pushing the membrane). Growing filaments attached to the endocytic
coat by tethering components (schematically shown in purple) create forces working in directions supporting further coated pit invagination. In (b), the
growth of tethered actin filaments, whose barbed ends face and are in tight contact with the plasma membrane, are physically limited in their extension.
This may lead to bending of actin filaments. The release of bending tension by filament straightening will move apart the two tether points and thereby
push the forming endocytic pit away from the plasma membrane deeper into the cytosol leading to progression of membrane invagination. In (c),
membrane-bound barbed end–directed myosins may either widen the space between the barbed end of actin filaments and the membrane and thereby
facilitate G-actin addition and/or may tilt filaments, whose barbed ends face and are in tight contact with the plasma membrane. Owing to such reorientation, the barbed end of the filament may become more easily available for G-actin addition. The resulting promotion of F-actin elongation would then
create forces increasing endocytic pit invagination.
Current Opinion in Cell Biology 2021, 68:10–19
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Membrane curvature and actin cytoskeleton Kessels and Qualmann
the signal of increased tension to the F-BAR domain
protein FBP17 by direct phosphorylation of the F-BAR
domain. This impaired both, FBP17 membrane binding
and shaping activity and additionally released the inhibition of mDia1-mediated actin stress fiber formation
thus coupling adaptive responses of membrane curvature and cytoskeletal organization [39]. In line with
previous reports for mDia1 inhibition [40], FBP17
deficiency reduced caveolar rosette density and consistently diminished the plasma membrane tension buffering capacity making the cells more vulnerable to
mechanical stress [39]. Tension-driven regulation of
BAR domain proteins might thus combine two mechanisms, intrinsic mechanosensitive properties [41] and
tension-triggered regulatory phosphorylation ensuring
that membrane-binding activity is haled upon increased
membrane tension.
Somewhat related is a mechanochemical feedback
model that might explain how membrane tension even
regulates the rhythmic assembly of both actin machinery and membrane-shaping proteins [42,43]. Low
membrane tension leads to increased recruitment of
FBP17. This recruitment in turn leads to an increase in
membrane curvature and thus to a positive feedback.
This would recruit even more FBP17 to the plasma
membrane. FBP17-stimulated N-WASP/Arp2/3ecomplex mediated actin polymerization then stiffens the
cortex creating a negative feedback loop by making the
membrane less deformable. This attenuates the
recruitment and action of the plasma membrane curvature and tension sensor FBP17. Thereby, the combination of positive and negative feedback mechanisms
might generate oscillatory behaviors [43].
The hen-and-egg causality dilemma(s)
Methodological advances have been made in recent
years to both visualize curvature-related processes in
in vitro reconstitutions, cells, and even tissues and to
induce distinct curvatures at artificial and cellular
membranes even in a dynamic manner [44]. Such
methods allow to get some new insights whether cytoskeletal elements and the intrinsically curved BAR
domain proteins primarily sense and thus follow or
whether they even actively cause membrane bending.
For the ERM protein ezrin, which binds both directly
and indirectly to membrane lipids and to actin filaments, the application of biomimetic model membranes
having different curvatures, purified proteins, and imaging methods including cryoelectron microscopy unveiled how ezrin might be localized to negatively
curved, positively curved, and to flat areas at the cell
cortex [45]. Interestingly, ezrin-mediated tethering of
lipid bilayers or targeting of ezrin to distinct curved lipid
surfaces both depended on protein conformations and
interactions with actin filaments, as well as I-BAR
domain proteins [46]. The I-BAR domain protein
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15
IRTKS has been suggested to localize to the distal tips
of actively growing microvilli in intestinal organoids
suggesting a role in curvature induction using either its
actin-binding WH2 domain or the recruitment of the
actin regulatory protein EPS8 in the Ls174T-W4 cell
line [47].
In contrast, in apolar neutrophils, initial breakages of
cell symmetry leading to a local increase in membrane
curvature occurred by cell contact to a surface and led to
a recruitment of the inverse F-BAR domain protein
SRGAP2. SRGAP2 in turn recruited downstream components including PI4KA and finally resulted in leukocyte cytoskeleton polarization [48].
Growing cells on engineered vertical nanostructures
(nanopillars or nanobars) as topographies had previously
already provided important insights into the recruitment of N-BAR domain proteins to externally induced
curvatures [49]. Related experiments recently revealed
that nanoscale topologies affect actin dynamics and organization both locally and rather globally. Actin filaments accumulated in a curvature-dependent manner,
and this was accompanied by Arp2/3 complex, cortactin,
and F-BAR domain protein accumulation [50]. It will be
interesting to see whether consecutive loss-of-function
studies will confirm an essential role of these proteins
and will thereby distinguish between ‘actors’ and ‘followers’. The global consequences for the cells, reductions in stress fibers, and mature focal adhesions may
be attributable to competition of the distinct F-actin
formation machineries for the same actin monomer pool.
A new system of dynamically light-induced curvature
induction at engineered nanostructures now even
allowed for analyzing protein responses to membrane
curvature changes in real time and thus provided a new
method to study curvature-sensitive processes in live
cells and to monitor kinetics of processes. Interestingly,
in contrast to membrane responses in milliseconds to
tens of seconds, the time scale for actin cytoskeletal
reorganizations was around 10 min [51]. Recently, an
optogenetic approach for light-inducible manipulation
of nanoscale membrane curvature in living cells has been
introduced by engineering a system that forces exogenously expressed BAR domainebased fusion proteins to
the plasma membrane [52].
Relieving the brake
In case that membrane shapers and actin cytoskeletal
forces are the initiators of membrane curvature, local
signals are required to define the sites of action. These
might be cell or matrix contacts, local inhomogeneities
in lipid distribution [15], transmembrane protein
composition or membrane tension, and/or special signals. These signals would then need to be decoded by
membrane shapers and/or the cytoskeleton resulting in
Current Opinion in Cell Biology 2021, 68:10–19
16 Cell Architecture
release of autoinhibition and/or activation of forcegenerating machineries. Extensive changes in membrane curvature promoting protrusion formation are
required in the development and plasticity of neurons.
These processes include new actin filament nucleation
[53], the action of intrinsically curved membraneshaping proteins including BAR domainecontaining
proteins, such as syndapins [54e56], and the newly
characterized curvature-sensing and introducing N-Ank
protein ankycorbin [57].
Adaptations of neuronal functions and shape are
prominently controlled by local calcium signals. A small
but rapidly growing set of actin nucleators and related
proteins is tightly controlled by the Ca2þ sensor protein
calmodulin (CaM) [56,58e60]. Important for dendritic
branching, Ca2þ/CaM association with the actin
nucleator Cobl controlled not only its interaction with
actin but furthermore suppressed Cobl’s direct lipid
binding and enhanced complex formation with syndapin I [56]. As a consequence, Cobl’s presence at the
plasma membrane during and subsequent to Ca2þ
transients becomes curvature sensitive [55,56]. Ca2þ/
CaM also directly binds to the N-BAR domains of
endophilins promoting their tubulation activity [61].
This may affect their role in promotion of actin polymerization in dendritic spines during synaptic potentiation [62].
Another important mechanism for spatiotemporal control represents the release of autoinhibition d a regulatory mechanism that is intriguingly commonly used in
both membrane shapers, particularly BAR domain proteins, and in F-actin formation machineries including
their activators. Presence or absence of protein regions
involved in autoinhibition due to alternative splicing was
suggested allowing F-BAR domain proteins to differentially localize and to either promote or inhibit neurite
outgrowth [63].
The physiological importance of autoinhibition mechanisms and their relief is highlighted by recent studies
on the functional consequences of a mutation in the FBAR domain of syndapin I (PACSIN1) found in patients with schizophrenia [64]. F-BAR interactions
were suggested to autoinhibit syndapin I’s SH3
domain functions [65,66]. In line, the schizophreniaassociated mutant of syndapin I was not only
impaired in membrane sculpting and association but
also exhibited neuromorphogenic deficits that coincided with a lack of membrane recruitment of cytoskeletal effectors including the Arp2/3 complex
activator N-WASP [67]. Consistently, syndapin I KO
mice [68,69] exhibited defects in dendritic arborization and developed schizophrenia-related behaviors.
This demonstrated the physiological relevance of such
molecular mechanisms not only for membrane bending
Current Opinion in Cell Biology 2021, 68:10–19
and cytoskeletal organization but also for functions of
whole organisms [67].
Conclusions and perspectives
Despite our knowledge about the general importance of
cytoskeletal organization and dynamics for membrane
topology for decades and despite the identification of a
plethora of molecular links between actin and (curved)
membranes d most prominently BAR domain proteins
d we have just begun to understand their delicate
interplay. As a further complication, the requirement
and degree of this interplay appears to be highly influenced by cell type and individual and/or transient
cellular conditions, such as membrane tension.
A major challenge for studies of the interplay between
membrane curvature and the cytoskeleton still remains
the unambiguous identification of membrane curvature
and the exact determination of its degree d particularly
in intact cells, tissues, or even organisms. Processes such
as endocytosis, caveolar invagination, or the formation of
protrusions, such as filopodia, cilia, or microvilli, require
curvature changes in the namometer scale. Thus, electron microscopical methods, in particular electron tomography and freeze fracturing in combination with
protein detection methods, are indispensable for correlating cytoskeletal organization with exact membrane
topology.
Furthermore, for understanding how forces of actin dynamics induce, propagate, and/or stabilize membrane
curvature, methods for highly resolved spatiotemporal
studies of actin dynamics in real time need to be further
developed. The same applies to the determination of
the polarity of individual actin filaments at the required
extremely high resolutions.
In addition, there still is only emerging evidence about
what is cause and what is consequence of membrane
curvature. Apart from this very fundamental question,
also the associated signaling and regulatory processes
largely remained elusive.
So far, we are furthermore lacking comprehensive
studies at the whole-organism level that shall ultimately
reveal the physiological importance of the interplay
between membrane curvature and the cytoskeleton and
provide an understanding of pathophysiological consequences of disruptions thereof.
Conflict of interest statement
Nothing declared.
Acknowledgements
The studies on membrane curvature and the cortical actin cytoskeleton
in the laboratories of the authors are supported by grant from the
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Membrane curvature and actin cytoskeleton Kessels and Qualmann
17
Deutsche Forschungsgemeinschaft to BQ (QU 116/6-2 and 9-1). This
agency had no role in the writing of the article or the decision to submit
it. The authors apologize that many studies on the interplay of membrane curvature and the cytoskeleton could not be covered and cited due
to space limitations.
18. Carlsson AE: Membrane bending by actin polymerization. Curr
Opin Cell Biol 2018, 50:1–7.
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