PERSPECTIVES

distribution of lipids in a bilayer can also

OPINION
affect membrane curvature.

Sheets, ribbons and tubules — Scaffolding proteins and membrane bending.

A protein or protein complex can form a
how organelles get their shape scaffold that bends the membrane of an
organelle. A growing number of proteins that
curve membranes by the scaffold mechanism
Gia K. Voeltz and William A. Prinz during vesicular fission or fusion have been
described (for recent reviews, see REFS 4,5).
Abstract | Most membrane-bound organelles have elaborate, dynamic shapes and These proteins bind to membranes transiently
often include regions with distinct morphologies. These complex structures are and oligomerize, forming rigid, curved struc-
relatively conserved throughout evolution, which indicates that they are important tures that bend the underlying membrane.
for optimal organelle function. Various mechanisms of determining organelle shape The oligomers disassemble when they are
have been proposed — proteins that stabilize highly curved membranes, the no longer needed. More permanent protein
scaffolds around organelles might help to
tethering of organelles to other cellular components and the regulation of
determine their shape. These could be gener-
membrane fission and fusion might all contribute. ated by integral membrane proteins, such as
caveolin, which oligomerizes, perhaps into
Phospholipid bilayers spontaneously form It has long been clear that a complex spirals, at the plasma membrane, resulting in
spherical or laminar shaped structures in interplay of factors determines organelle localized sites of membrane bending known
aqueous solution. Whereas some organ- morphology, but how this occurs, and the as caveolae (for a review, see REF. 6).
elles, such as lysosomes and peroxisomes, identity of the proteins responsible, has An integral membrane-protein scaffold
are relatively spherical, most have a remained unknown. Several recent studies might maintain the high curvature and
more complex shape. For example, the have begun to identify and characterize shape of the tubular cristae of the IMM.
Golgi complex and endoplasmic reticulum proteins that are required for shaping some The F1F0-ATP synthase is a conserved and
(ER) contain regions that form elaborate organelles. These findings indicate general highly abundant integral membrane-protein
networks of interconnected cisternae, mechanisms of organelle shaping that might complex in the IMM that has been proposed
tubules and fenestrations (FIG. 1). Other be used throughout the cell. Here we discuss to affect cristae structure by two mechanisms.
organelles, such as mitochondria and four of these mechanisms. First, some pro- The dimerization of the membrane-
multivesicular bodies, have outer limit- teins help to shape organelles by stabilizing imbedded F0 portions of the F1F0-ATP-
ing membranes and complex networks membrane curvature. Second, proteins that synthase complex might bend the IMM,
of internal membranes. Generating and tether membranes, either to the cytoskeleton perhaps by causing local deformations in
maintaining these and other highly curved or to other membranes, can also determine the membrane, thereby driving tubulation7,8.
organelle morphologies require specific organelle morphology. Third, the regulated In support of this function, interfering
mechanisms to stabilize them. fission and fusion of membranes can affect with the ability of the synthase to dimerize
The shape of most organelles is highly organelle shape. Last, some proteins can markedly alters the morphology of IMM in
conserved across species; similarly shaped help to determine organelle shape by stabi- yeast, converting the IMM tubular cristae
organelles are readily observed in yeast lizing different morphologies in continuous into onion-like structures9–12. The protein
and mammalian cells (FIG. 1). Also, differ- membranes. subunits that are required for dimerization
ent organelles can have subdomains that are not necessary for proton pumping by the
resemble each other in shape and architec- Stabilizing membrane curvature synthase, indicating that the onion-like struc-
ture. One example is the tubular networks Maintaining tubules, fenestrations, cisternae tures that are found in dimerization mutants
formed in regions of the ER and inner and other shapes with high curvature are not formed as an indirect result of defects
mitochondrial membrane (IMM) (compare requires proteins that bend membranes. in synthase function. The formation of IMM
FIG. 1c with FIG. 1e, and FIG. 2a with FIG. 2b). Three types of mechanism might be used tubules is also likely to be caused by oligo-
These networks not only look similar, but (FIG. 2c). In the first, a protein scaffold bends merization of the F1F0-ATP-synthase dimers
also have tubules with similar diameters in the underlying membrane. In the second, the into chains that might function as scaffolds;
numerous cell types (approximately 60 nm tendency of the two leaflets of a bilayer electron microscopy (EM) reveals that these
and 30 nm in diameter for ER and IMM to remain together, known as the bilayer- oligomers spiral around the IMM tubules
tubules, respectively1–3; FIG. 2a,b). This con- couple effect, can facilitate membrane bend- and therefore they might function as a rigid
servation indicates that these diameters are ing by proteins that insert domains into one membrane scaffold that shapes the bilayer7,13
probably important for organelle function. of the leaflets. In the third, the asymmetrical (FIG. 2a). The diameter of the IMM tubules

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© 2007 Nature Publishing Group
 PERSPECTIVES

a b might be determined by the rise and pitch of

the spirals formed during the oligomerization
of the F1F0-ATP-synthase dimers.
M
G Bilayer-couple effect. Some proteins might
M use the so-called bilayer-couple effect to
V G curve membranes and affect organelle shape.
As hydrophobic interactions between the
L
two leaflets of a membrane bilayer tend to
N G
keep them coupled together, a significant
change in the surface area of either leaflet,
N
perhaps by as much as a few percent5, causes
the membrane to bend. Proteins can there-
fore curve membranes by inserting into only
ER one (or primarily one) leaflet of a bilayer.
c d For an integral membrane protein to
induce or stabilize membrane curvature
throughout an organelle, it must be abun-
ER dant enough to encompass the entire region
ER tubule
of the organelle that is being actively shaped.
N
Such a mechanism has been proposed
recently for the reticulons and DP1/Yop1,
Lumen which are abundant integral membrane
proteins that are required to maintain proper
ER tubular structure14. These proteins have
NE
an unusual membrane topology; they insert
NE two pairs of α-helices partially into the ER
membrane. The hydrophobic stretches that
form the hairpin helices are not long enough
C
to completely span the membrane (they are
e f only 30–34 amino acids long). Therefore,
these short hairpins probably occupy more
ER space in the outer than the inner leaflet of
the ER membrane, causing it to curve and
tubulate14 (FIG. 2c).
Interestingly, these proteins have a similar
D topology to caveolin, which also inserts an
Golgi cis fingers unusually short hairpin into the membrane
stack
bilayer at the plasma membrane, and this
feature is at least partially responsible for
S generating membrane curvature at caveolae.
M Caveolin, the F1F0-ATP synthase, reticulons
and DP1/Yop1 therefore share several
trans cisternae proposed mechanistic features: they are all
trans ER oligomerizing integral membrane proteins,
they are concentrated at the region that they
Figure 1 | Organelles have complex, conserved shapes. Electron microscopy (EM) images of the yeast are shaping, and they have unusual
Pichia pastoris (a) and a mammalian normal rat kidney (NRK) cell (b) showing: the Golgi stack (G), nucleus transmembrane-domain properties that
(N), peripheral endoplasmic reticulum (ER), mitochondrion (M) and vacuole or lysosome (V or L). Note might generate membrane curvature.
the similar organelle shapes in both cells. Scale bar in a represents 0.5 μm and in b represents 1 μm. Tubule formation probably requires more
A confocal fluorescence image of a COS cell expressing an ER-localized protein labelled with green than an increase in membrane curvature, and
fluorescent protein (c). Both the nuclear envelope (NE) and the ER are formed from a single, continuous the abundant and oligomerizing reticulons
membrane. Scale bar represents 5 μm. EM image of an NRK cell highlights the even spacing (~50 nm) and DP1/Yop1 probably also use a scaffold-
of the two membranes of the NE (d); both are continuous with the tubular branches of the peripheral ing mechanism to stabilize tubules (this is
ER. Scale bar represents 0.2 μm. Single section of a three-dimensional tomogram of a chick dendrite
analogous to caveolin at caveolae and to the
mitochondrion (e). The boxed sections highlight the conserved ~20-nm spacing between the inner and
F1F0-ATP-synthase complex in mitochon-
outer mitochondrial membranes (S) and the ~30-nm diameter of cristae tubules (d). Scale bar represents
0.1 μm. EM image of an NRK cell showing the multiple cisternae of a Golgi stack (f). Note the regular drial tubules). The most logical arrangement
intercisternal spacing (~20 nm) and the irregular intracisternal lumenal spacing. Scale bar represents for all these proteins would be as spirals or
0.2 μm. Part a is reproduced with permission from REF. 54 © (1999) Rockefeller University Press. Part e is rings that encompass the region of the mem-
reproduced with permission from REF. 1 © (2000) Elsevier. Part c was kindly provided by J. Rist, Cambridge brane that they shape. These structures have
University, UK. Parts b, d and f were kindly provided by M. Ladinsky, University of Colorado, USA. not all been decisively demonstrated by EM.

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 8 | MARCH 2007 | 259

© 2007 Nature Publishing Group
PERSPECTIVES

Lipid asymmetry. Organelle morphology a b

might also be determined by lipids, some of
which cause negative or positive curvature in
membranes bilayers when they are asymmet-
rically distributed between the two leaflets.
The ability of a lipid to affect bilayer curvature
is determined by its effective shape in the
membrane; that is, the relative cross-sectional
area of its polar head group compared with
that of its apolar tail4. When these are similar,
for example, in phosphatidylcholine, the
lipid does not significantly affect membrane
curvature when it is enriched in one leaflet
of a bilayer. However, when the relative
areas of the head group and tail of a lipid c
differ, this can promote negative or positive
curvature when asymmetrically distributed in
a membrane. Examples of such lipids include Scaffold
phosphatidylethanamine, phosphatidic acid
and lysophosphatidylcholine. The significant
membrane deformations that occur during
vesicle formation and membrane fusion
Bilayer-couple effect
require that such curvature-promoting lipids
become transiently enriched in small regions Lumen
Lumen
of one leaflet of a membrane bilayer4,5,15.
Indeed, it has been proposed that some mem-
brane bending is driven by lipid asymmetries Lipid assymetry
that are generated by lipid-modifying
enzymes or by flippases, enzymes that transfer
Figure 2 | Making high-curvature membranes. a | Electron microscopy image of a Neurospora crassa
lipids between bilayer leaflets. For example,
mitochondrion showing the tubular-structure of the cristae of the inner mitochondrial membrane
phospholipase D, which hydrolyses phos-
(IMM). Tubules have a relatively constant diameter (~30 nm), intersect at three-way junctions (indi-
phatidylcholine to produce the curvature- cated by arrows) and have a lumen that is continuous with the intramembrane space (see red box).
promoting lipid phosphatidic acid, has Scale bar represents 100 nm. b | A confocal fluorescence microscopy image of a COS cell expressing
been implicated in several membrane- green fluorescent protein fused to the human reticulon RTN4a labels the peripheral endoplasmic
fusion reactions, although its function reticulum (ER) network of tubules. Tubules have a relatively constant diameter (50–100 nm) and
remains obscure16–18. intersect at three-way junctions (indicated by the arrow). Scale bar represents 200 nm. c | The high
The asymmetrical distribution of lipids curvature of organelle membranes can be generated by three mechanisms. In the first, an integral
that promote membrane curvature might membrane protein with its transmembrane domains inserted into the membrane bilayer oligomerizes
similarly help to determine organelle shape to form a protein scaffold with an angle of curvature. The surrounding membrane bilayer conforms
to the shape of the rigid protein scaffold. In this example, the scaffold is formed from dimers of the
(FIG. 2c). However, unlike vesicle budding and
F1F0-ATP synthase (shown in red, orange and yellow). These can form higher order oligomers with
fusion, the membrane deformations required
spiral structures that might tubulate the IMM (right). In the second, a protein might occupy a larger
for maintaining organelle structures are not area in the outer leaflet of a membrane than in the inner leaflet, causing it to curve because of the
transient and must occur over entire domains bilayer-couple effect, a phenomenon in which hydrophobic interactions between the two leaflets of
of an organelle. There is little evidence that a membrane bilayer tend to keep them coupled together. Reticulon proteins might generate curva-
curvature-promoting lipids are significantly ture in ER tubules by this mechanism. In the third, the asymmetrical distribution of lipids between the
and continuously asymmetrically distributed leaflets of a membrane bilayer can generate curvature. For example, more or larger phospholipids in
in most organelle membranes other than the outer leaflet increase the surface area relative to that of the inner leaflet and introduce curvature
the plasma membrane. Some organelles into the membrane. Part a is modified with permission from REF. 2 © (2000) Elsevier. Part b was kindly
with elaborate shapes, including the ER and provided by J. Rist, Cambridge University, UK.
the cis-Golgi complex, are thought to have
energy-independent flippases that rapidly
equilibrate most, if not all, classes of lipid Cytoskeletal tethering. In higher eukaryotes, binding to the cytoskeleton have been
in the membrane19–21. It therefore seems many organelles, including the ER, mito- identified. One example is the complex
unlikely that lipid asymmetries make a chondria and the Golgi complex, bind to of dynein and dynactin that attaches the
significant contribution to determining the the cytoskeleton. These interactions facili- Golgi complex to microtubules. Disruption
shape of these, or most other, organelles. tate organelle movement and positioning of this complex causes marked changes in
in cells but might also help to determine Golgi shape and localization; short Golgi
Membrane tethering organelle morphologies, which can become stacks form near ER-exit sites22. A similar
The attachment or tethering of membranes severely altered when microtubules or actin phenotype is seen when microtubules are
to each other or to the cytoskeleton can also filaments are depolymerized. In some cases, disrupted23. However, these changes could
help to determine organelle shape. proteins that are required for organelle be indirect because vesicular trafficking to

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© 2007 Nature Publishing Group

a Tethering membrane to cytoskeleton
Microtubule
b Tethering apposing membranes
c Tethering apposing membranes to each other
and to the cytoskeleton
Cytoplasm Actin
ONM
N and maintaining the distribution of ER
LINC PNS ~50 nm NE
S S
INM
Nucleoplasm Lamins
Figure 3 | Membrane tethering generates
organelle shape by three mechanisms.
a | Tethering the membrane to components of the
cytoskeleton, such as microtubules, can deter-
mine organelle shape. An integral membrane
protein (red cylinder) can bind to an adaptor
protein (green oval) on microtubules to allow
cytoskeleton-dependent rearrangements of
organelle shape. b | Tethering membranes to each
other can shape and stack membranes. Stacked
cisternae can be generated by dimerization of
integral membrane proteins (red cylinders) that
are present in apposing membrane bilayers.
c | Tethering two membranes to each other and to
the cytoskeleton shapes the nuclear envelope
(NE). The LINC complex is shown. This comprises
the SUN (Sad1 and UNC-84 homology domain)
proteins (S), which accumulate in the inner
nuclear membrane (INM) owing to interactions
with the nuclear lamina. SUN proteins bridge the
perinuclear space (PNS) and bind nesprins (N),
which are located in the outer nuclear membrane
(ONM). The SUN–nesprin complex helps to deter-
mine the highly conserved spacing between the
INM and the ONM (~50 nm). The nesprins are also
anchored to actin surrounding the NE.
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
the Golgi complex, which requires dynein,
dynactin and microtubules, is needed to
maintain Golgi shape24. Mitochondrial
shape is also affected by both microtubule
and actin-filament disruption. In both
cases, these changes also seem to be due
to loss of trafficking, specifically of the
fission protein dynamin-related protein-1
(DRP1; known as Dnm1 in yeast)25,26. Actin
filaments might have a more direct role
in maintaining Golgi shape; conditions
that cause actin depolymerization without
disrupting vesicular trafficking cause Golgi
stacks to fragment and result in swelling of
cisternae27.
The contribution of the cytoskeleton
to ER structure also remains unclear.
Microtubules often align with the tips of
growing ER tubules and might be required
to extend new tubules from the ER (FIG. 3a).
Cytoskeleton-linking membrane protein
CLIMP63 (previously known as p63) is an
integral ER-membrane protein that binds
microtubules, and is currently the best can-
didate protein for mediating this interaction.
Overexpression of CLIMP63 that lacks the
microtubule-binding domain causes the ER
membranes to retract towards the nuclear
envelope and a reduction in ER tubular
structures28. Although microtubules and
CLIMP63 might contribute to extending
tubules throughout the cytoplasm, it seems
unlikely that they maintain ER shape; after
ER tubules form, they rarely align with
microtubules and there is a lag of many min-
utes between microtubule depolymerization
and alterations in organelle shape (this is
also true for the Golgi complex). Moreover,
ER tubules can be formed in vitro in the
absence of microtubules3,29–31. Other factors
might be the primary determinants of
organelle morphology, and microtubules
could be required mostly for proper
dispersal of organelles in the cell.
Intermembrane tethering. Attachments
between membranes can also help to
determine organelle shape. In some cases,
these attachments cause membranes to form
closely apposed sheets (FIG. 3b). For example,
tethering helps to generate the ER cisternae
that are seen in some cell types. Snapp and
co-workers showed that low-affinity inter-
actions between cytosolic domains of ER-
membrane proteins promote the formation
of stacked ER cisternae with a fixed distance
between membranes32.
Other examples of membrane tethering
that are required for proper organelle struc-
ture come from mitochondria. The lumenal
© 2007 Nature Publishing Group
PERSPECTIVES
spacing between the sheets of the outer
mitochondrial membrane and the IMM is
regular (~30 nm) and is probably deter-
mined, at least in part, by the rigidity and
shape of the abundant TIM/TOM (trans-
locases of inner and outer mitochondrial
membrane) translocation complex, which
spans both membrane bilayers33. Membrane
tethering might also help to determine the
structure of IMM cristae. It has been pro-
posed that oligomerization of membrane
bound and soluble forms of the IMM-
localized dynamin-like protein optic
atrophy protein-1 (OPA1; known as Mgm1
in yeast) can help to determine cristae
shape by tethering these membranes to
each other. Depletion of OPA1 results in a
marked reorganization of the IMM and
the loss of cristae tubules34,35.
The organization of Golgi stacks almost
certainly requires membrane tethering.
Whereas the intralumenal spacing in Golgi
cisternae can vary across the stack from cis
to trans (from 15–30 nm for cis-Golgi and
from 4–11 nm for trans-Golgi in a plant
cell36), the intercisternal spacing in Golgi
stacks is regular 37 (~20 nm, see FIG. 1f).
An integral membrane-protein matrix
probably generates this distance. Indeed,
treatment of isolated Golgi stacks with some
proteolytic enzymes causes unstacking of
cisternae38. Furthermore, EM has revealed
organized rows of proteins on the surface
of the Golgi stacks that is consistent with an
integral membrane-protein-matrix struc-
ture, although the identity of these proteins
is not known36.
Tethering to the cytoskeleton and membranes.
Membranes can be simultaneously teth-
ered to both other membranes and the
cytoskeleton (FIG. 3c). The LINC complex
provides a good example of this. This
complex, which spans both membranes of
the nuclear envelope, comprises SUN (Sad1
and UNC-84 homology domain) proteins
in the inner nuclear membrane (INM) and
nesprins in the outer nuclear membrane.
The N terminus of each SUN protein inter-
acts with nuclear lamins, holding the
SUN proteins in the INM, whereas the
C terminus binds nesprins in the perinu-
clear space (PNS), forming a complex that
spans the PNS. On the cytoplasmic face of
the nuclear envelope the nesprins, in turn,
interact with the actin cytoskeleton. The
entire complex determines, at least in part,
the shape and spacing of the inner and outer
nuclear membranes (the PNS is ~50-nm
wide); depletion of the SUN proteins results
in the expansion of the PNS39–41.
VOLUME 8 | MARCH 2007 | 261
PERSPECTIVES

Less fission Wild type Less fusion that maintains the shape of these organelles
is probably regulated. There is some
evidence that, for all three of these mem-
Δdnm1 Δfzo1
brane systems, this fusion requires compo-
nents of a fusion machinery that includes
Deletion of MFN1 p97 (also known as valosin-containing
protein (VCP)) and VCIP135, as antibod-
ies against these proteins can prevent the
assembly of tubular ER, Golgi stacks and the
nuclear envelope in vitro46–49. Presumably
the ability of these proteins to promote
fusion is regulated by phosphorylation or
another post-translational modification
during the cell cycle.
b Another way in which regulated fusion
Golgi stacks Golgi stack ribbon
affects organelle morphology has recently
Medial Medial Medial Medial
been described. The Golgi complex is often
arranged as stacks of biochemically distinct
cisternae. Some cell types have several of
these stacks (FIG. 1a) and in most vertebrate
cells the stacks are linked together to form
ribbons. This process requires fusion of
lateral cisternae while still maintaining the
Fusion integrity of the stacks (that is, making sure
GRASP65
that all the stacks do not fuse together).
Puthenveedu et al. have found that a com-
plex of proteins including Golgi reassembly
GM130 stacking protein of 65 kD (GRASP65) and
the cis-Golgi matrix protein of 130 kD
(GM130) tether lateral cisternae together,
cis cis cis cis
thereby promoting their fusion50 (FIG. 4b).
The proper shape of the Golgi stack is
Figure 4 | Balancing fission and fusion affects organelle shape. a | Mitochondrial shape is regulated therefore maintained by promoting fusion
by fission and fusion. Each panel shows mitochondria, labelled with green fluorescent protein, in a at specific regions of cisternae.
single Saccharomyces cerevisiae cell. In wild-type cells, mitochondria form branched networks of
tubules (middle panel). Cells that lack a fusion-promoting protein fuzzy onions-1 (Δfzo1) contain
Differently shaped domains
numerous small mitochondria (right panel). Deletion of the gene for another fusion protein, mito-
fusin-1 (MFN1), generates a similar phenotype. Cells that lack a protein needed for fission, dynamin- Many organelles not only have complex
related protein-1 (Δdnm1), form large fenestrated mitochondria (left panel). A schematic of the morphologies, but also maintain domains
mitochondrial phenotypes is shown below. b | The continuity of the Golgi-stack ribbon is promoted in the organelle with different shapes.
by a fusion machinery associated with the oligomerization of Golgi matrix protein of 130 kD (GM130; Perhaps the most striking example is the
red rectangles) and Golgi reassembly stacking protein of 65 kD (GRASP65, green triangles). These peripheral ER, which is formed from a
proteins promote fusion between analogous cisternae to laterally link adjacent Golgi stacks. single membrane and is continuous with
Cisternae from the cis-Golgi (yellow) and medial-Golgi (green) are shown. Conversely, altering the nuclear envelope, but can have domains
the amounts of these proteins results in fragmentation of the Golgi ribbon into individual stacks. that are tubulated, fenestrated or form
Part a is modified with permission from REF. 45 © (2001) Elsevier.
stacked cisternae51,52 (FIG. 1c,d). How differ-
ently shaped regions are maintained in a
single membrane is not well understood,
Regulating fission and fusion of a few large, fenestrated mitochondria42,43 but at least three mechanisms are thought
Organelle membranes are dynamic and (FIG. 4a). Remarkably, when both fusion and to be responsible (FIG. 5). One is a selective
constantly undergo both fusion and fission fission are blocked in cells that lack Fzo1 diffusion barrier mechanism, which might
reactions. Not surprisingly, these processes and Dnm1, mitochondria look similar to prevent membrane-shaping proteins or
can profoundly affect organelle shape. those of wild-type cells. Mitochondrial lipids from moving between different
A particularly telling example is provided shape is therefore maintained by balancing organelle domains. A septin-dependent dif-
by mitochondria. Mitochondria continu- the rates of fusion and fission44,45. fusion barrier in the ER at the neck of bud-
ally fuse with each other and divide. When In response to environmental stress, or ding yeast cells has recently been described;
fusion is blocked, by depleting the proteins during the cell cycle, the balance of mem- this barrier slows diffusion of membrane
mitofusin-1 (MFN1) or its yeast homologue, brane fusion and fission can often modulate proteins between the continuous ER of
known as fuzzy onions-1 (Fzo1), or OPA1/ organelle morphology. For example, the ER, mother and daughter cells53.
Mgm1, numerous small mitochondria nuclear envelope and Golgi complex can Membrane tethering probably represents
accumulate. By contrast, blocking fission, completely disassemble during mitosis and a second mechanism of generating
by depleting Dnm1, causes the formation then must reform. The homotypic fusion differently shaped regions of organelles.

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© 2007 Nature Publishing Group

a Diffusion barrier
Plasma membrane
S ity of the membrane. b | The spherical shape of the
ER
b Membrane tethering to object
NE
Nuclear
lamina
Chromatin
c Inherent shape segregation
For example, proteins residing in the INM
can be tethered to other nuclear compo-
nents, including lamins and chromatin,
which probably helps to keep this mem-
brane a different shape compared with the
mostly tubular peripheral ER51.
Last, membrane-shaping proteins them-
selves could generate differently structured
organelle regions by segregating primarily
into part of the organelle. For example, it
might be energetically unfavourable for
proteins that stabilize curved membranes to
diffuse out of them into less curved regions
of an organelle. Such a mechanism has been
proposed for the reticulons that are highly
enriched in tubulated portions of the ER14.
Remarkably, this is true even when these
proteins are overexpressed. Therefore, the
affinity of reticulons for tubulated mem-
branes might ensure that regions of the ER
that are devoid of reticulons can assume
shapes other than tubules, such as sheets of
the peripheral ER and nuclear envelope.
Concluding remarks
We are still only beginning to understand
how complex organelle shapes are gener-
ated. Membrane-bending proteins, such
as the reticulons, DP1/Yop1 and caveolin
probably have a central role in generating
shape in many organelles. The most impor-
tant challenge for the future remains under-
standing how these proteins function and
are regulated. Another intriguing question
NATURE REVIEWS | MOLECULAR CELL BIOLOGY
Figure 5 | Three mechanisms of maintaining
differently shaped domains in a membrane.
a | A septin ring (S) located at the bud neck of a
yeast cell prevents rapid diffusion of membrane
proteins between the endoplasmic reticulum (ER)
of mother and daughter cell, despite the continu-
nuclear envelope (NE) might be partly determined
by tethering inner nuclear membrane proteins
(red rectangles) to the nuclear lamina and to chro-
matin. Tethering of the inner nuclear membrane
to the condensed and roughly spherical nuclear
contents confers a spherical shape to the nuclear
envelope and prevents tubulation of the NE by
other shaping factors (for example, reticulons).
c | A membrane-shaping protein partitions into
one domain of a membrane because of its affinity
for membranes of a particular shape. Here, reticu-
lon proteins (red) shape ER tubules and localize
exclusively to tubules even when overexpressed.
The shape of these proteins might make it ener-
getically more favourable for them to localize to
highly curved membranes, such as tubules.
Conversely, the shape of the reticulon might also
prevent it from diffusing into membranes of low
curvature, such as the sheets of the NE, and
therefore the shape of the NE is also maintained.
is the relationship between organelle shape
and optimal organelle function. As more
organelle-shaping proteins are identified,
it will be possible to assess this relation-
ship more directly and, in particular, to
understand how organelle morphology is
regulated both during the cell cycle and
during cellular differentiation.
Gia K. Voeltz is at the Department of Molecular,
Cellular, and Developmental Biology, University of
Colorado, Boulder, Colorado 80309, USA.
William A. Prinz is at the Laboratory of Cell
Biochemistry and Biology, National Institute of
Diabetes and Digestive and Kidney Diseases,
National Institutes of Health,
United States Department of Health and
Human Services, Bethesda,
Maryland 20892, USA.
e-mails: gia.voeltz@colorado.edu;
wprinz@helix.nih.gov
doi:10.1038/nrm2119
Published online 7 February 2007
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Acknowledgements
We thank M. Ladinsky and J. Rist for providing images, and Y.
Shibata and J. Hinshaw for reading the manuscript. W.P. was
supported by the Intramural Research Program of the National
Institute of Diabetes and Digestive and Kidney Diseases.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
The following terms in this article are linked online to:
UniProtKB: http://ca.expasy.org/sprot
DRP1 | GM130 | GRASP65 | MFN1 | OPA1 | p63 | VCIP135 |
VCP | Yop1
Access to this interactive links box is free online.
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