The Superlattice Model of
Membrane Lateral Organization
Implications on Lipid Compositional
Regulation and Maintenance of
Organelle Boundaries
INTRODUCTION
•
•
•
•
•
•
•
•
•
•
•
It is unknown how cells regulate the lipid composition of their membranes.
Overexpression of the rate limiting biosynthetic enzymes does not increase significantly the
concentration of the corresponding phospholipids.
This is because (unknown) phospholipases are activated and rapidly degrade the phospholipid in
excess, but it is not known what triggers/inhibits the activity of those phospholipases.
The activities of both the synthetic enzymes and phospholipases must be closely coordinated to
avoid futile competition
Such coordination might be achieved via the action on some proteins that sense the
concentration of the individual lipids, but such proteins have not been described so far
We and others have proposed that the different lipid species in multicomponent membranes tend
adopt regular (even) lateral distributions (Somerharju et al., 1999; Chong & Sugar, 2001).
This putative phenomenon, referred to as lipid superlattice (SL) formation, predicts that there
are several “critical”, energetically favorable compositions
Such critical composition could play a key role in the regulation of the lipid composition of
cellular membranes by inhibiting/activating synthetic enzymes and phospholipases in a
coordinated manner
The superlattice-based regulation mechanism is supported by that the phospholipid composition
of the erythrocyte membrane falls were close to a critical composition predicted by the SLmodel (Virtanen et al.1998).
Intriguingly, the SL-model could also help to explain how cells maintain the integrity or their
organelles. The model namely predicts that when a critical concentration of a phospholipid (or
cholesterol) is exceeded (e.g. due to ongoing synthesis), segregation of domains with different
SL-compositions takes place.
Such segregation can drive membrane budding (Julicher & Lipowsky, 1993) and could thus be
the basis of organelle integrity. Perhaps even the existence of separate Golgi compartments
could be based on this principle?
Phospholipid composition of mammalian
membranes are influenced by:
A. Activity of rate-limiting synthetic enzymes
•
Cytidyltransferase (influenced by e.g. PC content and membrane charge)
•
PS-synthase (influenced by e.g. PS content or membrane charge)
B. Activity of phospholipases
•
Overexpression of Cytidyltransferase => PC does not increase (Walkey et al. 1994)
•
Overexpression of Ethanolamine kinase => PE does not increase (Lydikis et al. 2001)
•
Overexpression of PS-Synthase => PS does not increase (Stone et al. 1998)
•
Increased amounts of degradation products in medium!
What is the primary regulatory factor?
A. Multiple regulatory proteins?
Synthesis ↑↑ PC
PC ↓↓ degradation
Degradation
Synthesis
Synthesis ↑ PE ↓ Degradation
PC-Regulator
PC-Regulator
PE- Regulator
??
PS-Regulator
Synthesis ↑ PS ↓ Degradation
PI- Regulator
Synthesis ↑ PI↓ Degradation
?? = How can all these enzymes be coordinated to avoid futile
competition between synthetic and degradative machineries?
Alternative model: Tendency of lipids to abopt regular
distributions (i.e. superlattice formation) coordinates
synthesis and degradation
 Only a limited number of allowed compositions!
15.4 %
25 %
50%
Superlattices are minimum energy structures
(i.e. not permanent or rigid)
.......because they..
1. Allow tightest packing of the lipids
(Enthalpic effect) =>
2. Avoid proximity of charged lipids
(Coulombic effect) =>
3. Increase rotational freedom of headgroups
(Entropic effect) =>
How could Superlattice formation control lipid
compositions?
•
Superlattice compositions are local energy minima and thus inherently
more stable than other compositions
SL
•
Order/disorder transitions could
activate/inhibit synthetic enzymes =>
Dissolved enzyme =
active
..and phospholipases as well =>
Phospholipase acts
Aggregated enzyme
= inactive
Supporting evidence: Phospholipid composition of erythrocyte
membrane is compatible with the SL-model
Assumption: Phospholipids can be
divided into 3 classes:
1) Choline phospholipids (CP) = SM + PC
Large headgroup
2) Ethanolamine phospholipids = PE
Small headgroup
3) Acidic phospholipids (AP) = PS ( PI, PA)
Negatively charged headgroup
In 3-component superlattices the crical concentrations are Multiples of 11.1 mol% !
Phospholipid composition of the erythrocyte membrane
CPs
PE
APs
Outer
Leaflet
Inner
Leaflet
88.9
88.9
23.1
22.2
(77.8 < > 100)
(11.1 < > 33.3)
11.1
11.0
43.9
44.4
(0 < > 22.2)
(33.3 < > 55.5)
0.0
0.0
32.9
33.3
Outer
Inner
(22.2 < > 44.4)
Black = Experimental (Dogde & Phillips, J. Lipid Res. 8,667, 1967)
Red = Predicted by SL-Model (Virtanen et. Al. PNAS 95, 4964, 1998)
• Cholesterol supplements PE as a headgroup spacer in OL?
• Superlattices also help to maintain transversal membrane asymmetry?
SL-model and maintenance of organelle boundaries
• Domain segregation is known to drive budding and fission of
vesicles in model systems (e.g., Julicher and Lipowsky 1993)
• SL-model predicts that domains with different SL-compositions do
not mix
• Ongoing lipid synthesis in ER could result partial conversion of the
ER-SL to another one resulting in segregation of domains and
budding of those domains as vesicles forming the Golgi membranes
• The existence of several Golgi compartments could be based on
subsequential segregation of different SL-domains. The stacks do
not fuse because the different SLs do not like to mix
• The lipid composition of raft domains in the PM of nucleated cells
could correspond to that of the erythrocyte membrane
Conclusions
•
•
•
•
Experiments with model membranes and theoretical arguments suggest that
lipids in natural membranes have a significant tendency to adopt regular
distributions
Such a tendency could play a key role in synchronizing lipid synthesis and
degradation thus maintaining membrane lipid compositions
Different organelle membranes could have different superlattices, which
could help to maintain the integrity of the organelles, particularly those
connected to each other via constant vesicle flow
Rafts are proposed to have a superlattice organization which is similar to
that suggested previously for the erythrocyte membrane
REFERENCES
Chong PL, Sugar IP. Fluorescence studies of lipid regular distribution in membranes. Chem Phys Lipids. 2002 Jun;116(1-2):153-75.
Julicher F, Lipowsky R. (1993) Domain-induced budding of vesicles. Phys Rev Lett. 70:2964-2967
Lykidis A, Wang J, Karim MA, Jackowski S (2001) Overexpression of a mammalian ethanolamine-specific kinase accelerates the
CDP-ethanolamine pathway. J Biol Chem. 276:2174-9.
Somerharju, P., Virtanen, J.A. and Cheng, K.H. (1999) Lateral organisation of membrane lipids. The superlattice view. Biochim. Biophys. Acta 1440,32-48
Stone SJ, Cui Z, Vance JE. (1998) Cloning and expression of mouse liver phosphatidylserine synthase-1 cDNA. Overexpression in rat hepatoma
cells inhibits the CDP-ethanolamine pathway for phosphatidylethanolamine biosynthesis. J Biol Chem. 273:7293-302.
Virtanen, J. A., Cheng, K. H. and Somerharju, P. (1998) Phospholipid composition of the erythrocyte membrane can be rationalized by a lipid head group
superlattice-model. PNAS 95, 4964-4969
Walkey CJ, Kalmar GB, Cornell RB. (1994) Overexpression of rat liver CTP:phosphocholine cytidylyltransferase accelerates phosphatidylcholine
synthesis and degradation. J Biol Chem. 269:5742-9.