NEN5000 #03

Internal Organization of the Cell:

Membrane Structure

The da Rocha Group

Schematic of Cell Surface: Complexity!

NATURE CHEMISTRY | VOL 3 | AUGUST 2011

The da Rocha Group
 Motivation
 How do therapeutics or nanocarriers
(prodrug) get access to the intracellular
environment?
 How can the molecular biology of the cell
be explored to our advantage –
enhanced / or more specific (targeting)
delivery…

J. AM. CHEM. SOC. 2010, 132, 5761–5768 9 The da Rocha Group

 Targeting Membrane Proteins
Prostate-specific membrane antigen
(PSMA): a protein found on the membrane
of more than 90% of all prostate cancers.
Aptamers: RNA or DNA molecules selected
from random pools based on their ability to
bind other molecules, including small organic
compounds, nucleic acids, and proteins.
PSMA: can be targeted with
“Aptamers”, which may carry the
payload specifically to cancerous
cells…
Journal of Nucleic Acids, 2011
http://www.labgrab.com
The da Rocha Group
 Lots of receptors… and other mechanisms
for cellular drug delivery…

… all involve first interaction with the cell membrane surface!

Biochimica et Biophysica Acta 1798 (2010) 2190–2200

The
Advanced Drug Delivery Reviews 63 da Rocha
(2011) 3–23 Group
 Cell Membranes: Relevance

Cell membranes are crucial to the life of the cell. The plasma
membrane (A)
(i) encloses the cell
(ii) defines its boundaries, and
(iii) maintains the essential differences between the
cytosol and the extracellular environment.

The da Rocha Group

 Cell Membranes: Relevance

Relevance: Cell membranes are crucial to the life of the

cell.
Inside eukaryotic cells (B), the membranes of the
(i) endoplasmatic reticulum (ER),
(ii) Golgi apparatus,
(iii) mitochondria and
(iv) other membrane-enclosed organelles
maintain the characteristic differences between the
contents of each organelle and the cytosol  can represent
significant challenges in drug
delivery…

The da Rocha Group

General Structure of Biological
Membranes: The Lipid Bilayer
Cell membranes:
(i) very thin films consisting of lipids and protein molecules, held
together mainly by noncovalent interactions
(ii) They are dynamic, fluid structures, and most molecules move
about in the plane of the membrane.

The da Rocha Group

General Structure of Biological
Membranes: The Lipid Bilayer
LIPID LAYER:
(i) double layer ca. 5 nm thick
(ii) provides basic structure of the membrane
(iii) impermeable barrier to the passage of most water-soluble molecules
(iv) structure arises due to ability of lipid to “self-assemble”

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General Structure of Biological
Membranes: Cholesterol – also a major component

Glycerol  in the lipid bilayers in many cell membranes…

up to 1:4 cholesterol:lipid

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Lipid Bilayer is a 2D Fluid

Rapid Lateral diffusion

 10-8 cm2/sec =
exchange rate with
neighbor  107 times /
sec ! = ca. 1sec to travel
the length of a large cell
(e.g. bacterial cell)
Rare flip-flop  but
catalyzed by certain
proteins to populate non-
cytosolic side of bilayer!
As it is produced intra-
cellularly …
The da Rocha Group
Asymmetry of Bilayer is
Functionally Important
Lipid composition of the two monolayers of the lipid bilayers in
many membranes are strikingly different  this asymmetry is
important to convert extracellular signals into intracellular signals
e.g. (1) in red blood cells lipids with negative head-group in the
cytosolic side!

(2) Apoptosis  during programmed cell death,

phophatidylserine, which is normally confined to cytosolic
monolayer, rapidly translocates to the extracellular monolayer 
it signals to macrophages to phagocyte the cell!
The da Rocha Group
Transmembrane Proteins…
… mediate nearly all of the other functions of the membrane 
(i) transport of specific molecules
(ii) structural links  cytoskeleton to extracellular matrix or other cells
(iii) receptors from cell environment
(iv) ca. 30% of all proteins are transmembrane proteins

The da Rocha Group

Transmembrane Proteins…
… many are glycosylated
 Because most plasma membranes are glycosylated,
carboxylates extensively coat the surface of all eucaryotic cells!
 Carbohydrate coat (glycocalyx)  covalently bound to proteins
(glycoproteins) and lipids (glycolipids)!

The da Rocha Group

Transmembrane Proteins…
… can diffuse in the plane of the membrane
They do not flip-flop, but they rotate about an axis
perpendicular to the plane of the bilayer (rotational diffusion),
and they are also able to move laterally (lateral diffusion)
… cells can confine proteins and lipids to specific
domains within a membrane
 Many cells confine membrane proteins
to specific regions within the
continuous bilayer!
 In epithelial cells, such as those that
line the gut or the tubules of the
kidney, certain plasma membrane
enzymes and transport proteins are
confined to the apical surface of the
cells The da Rocha Group
 Main Source
Molecular Biology of the Cell
Chapter 10: Membrane Structure
Alberts et. al., ISBN: November 16, 2007 | ISBN-
10: 0815341059 | ISBN-13: 978-0815341055 |
Edition: 5
“For nearly a quarter century Molecular Biology of
the Cell has been the leading cell biology textbook.
This tradition continues with the new Fifth Edition,
which has been completely revised and updated to
describe our current, rapidly advancing
understanding of cell biology. To list but a few
examples, a large amount of new material is
presented on epigenetics; stem cells; RNAi;
comparative genomics; the latest cancer therapies;
apoptosis (now its own separate chapter); and cell
cycle control and the mechanics of M phase (now
integrated into one chapter).” Review from Amazon
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 Questions

(5) Find a peer reviewed article (provide

link) on PSMA targeting with a
nanoparticle. Describe the targeting
moiety and the type of nanocarrier.
(6) For an epithelium: provide a
schematic diagram of the epithelial
barrier; indicate the apical and
basolateral side; define polarization of
that barrier.
The da Rocha Group