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Biochemistry: A Short Course

First Edition

Biochemistry: A Short Course

First Edition

Tymoczko • Berg • Stryer

© 2010 W. H. Freeman and Company

CHAPTER 11

Membrane Structure and Function

Phospholipids and Glycolipids Readily Form

Phospholipids and Glycolipids Readily Form

Bimolecular Sheets in Aqueous Media

Bimolecular Sheets in Aqueous Media

What properties enable phospholipids to form

membranes? Membrane formation is a consequence

of the amphipathic nature of the molecules.

Their polar head groups favor contact with

water, whereas their

hydrocarbon tails interact with one another, in

preference to water.

How can molecules with these preferences

arrange themselves in aqueous solutions? One

way is to form a micelle , a globular

structure in which polar head groups are

surrounded by water and hydrocarbon tails are

sequestered inside, interacting with one

another

Proteins Associate with the Lipid Bilayer in a

Proteins Associate with the Lipid Bilayer in a

Variety of Ways

Variety of Ways

Membrane proteins can be classified as being either

Membrane proteins can be classified as being either

peripheral

peripheral or

or integral

integral on the basis of this difference in

on the basis of this difference in

dissociability.

dissociability.

Integral membrane proteins

Integral membrane proteins interact

interact extensively with the

extensively with the

hydrocarbon chains

hydrocarbon chains of membrane lipids, and so only agents

of membrane lipids, and so only agents

that compete for these

that compete for these nonpolar interactions can release

nonpolar interactions can release

them

them .

peripheral membrane proteins

peripheral membrane proteins are

are bound

bound to membranes

to membranes

primarily by

primarily by electrostatic and hydrogen-bond

electrostatic and hydrogen-bond interactions

interactions

with the head groups of lipids. These polar interactions

with the head groups of lipids. These polar interactions

can be disrupted by adding salts or by changing the pH.

can be disrupted by adding salts or by changing the pH.

bound to the surfaces of

bound to the surfaces of integral proteins

integral proteins , on either the

, on either the

cytosolic or the extracellular side of the membrane.

cytosolic or the extracellular side of the membrane.

Others are

Others are anchored to the lipid bilayer

anchored to the lipid bilayer by a covalently

by a covalently

attached hydrophobic chain, such as a fatty acid.

attached hydrophobic chain, such as a fatty acid.

Amino Acid Sequence of

Amino Acid Sequence of

Bacteriorhodopsin. The

Bacteriorhodopsin. The seven

seven

helical regions are highlighted

helical regions are highlighted

in yellow

in yellow and the

and the charged

charged

residues in red.

residues in red.

A Channel Protein Can Be Formed from

A Channel Protein Can Be Formed from Beta Strands

Beta Strands

Porin,

Porin, a protein from the outer membranes of bacteria

a protein from the outer membranes of bacteria

such as

such as E. coli

E. coli and

and Rhodo-bacter capsulatus

Rhodo-bacter capsulatus , Structures

, Structures

of this type are built from β strands and contain

of this type are built from β strands and contain

essentially no α helices

essentially no α helices

each strand is hydrogen bonded to

its neighbor in an antiparallel

arrangement, forming a single β

sheet. The β sheet curls up to

form a hollow cylinder that

functions as the active unit. As

its name suggests, porin forms

pores, or channels, in the

membranes. The outside surface of

porin is appropriately nonpolar,

given that it interacts with the

hydrocarbon core of the membrane.

In contrast, the inside of the

channel is quite hydrophilic and

is filled with water. This

Embedding Part of a Protein in a Membrane Can Link It to

Embedding Part of a Protein in a Membrane Can Link It to

the Membrane Surface

the Membrane Surface

prostaglandin H

prostaglandin H

2

2

synthase-

synthase- -different

-different

role for α helices in protein-membrane associations. This

role for α helices in protein-membrane associations. This

enzyme catalyzes the conversion of

enzyme catalyzes the conversion of arachidonic acid

arachidonic acid

into

into prostaglandin H

prostaglandin H

2

2

.

. Prostaglandin H

Prostaglandin H

2

2

promotes

promotes

inflammation

inflammation and

and modulates gastric acid secretion.

modulates gastric acid secretion.

not largely embedded in the membrane but, instead,

not largely embedded in the membrane but, instead, lies

lies

along the outer surface of the membrane firmly bound by a

along the outer surface of the membrane firmly bound by a

set of α helices

set of α helices with hydrophobic surfaces that extend

with hydrophobic surfaces that extend

from the bottom of the protein into the membrane This

from the bottom of the protein into the membrane This

linkage is sufficiently strong that only the action of

linkage is sufficiently strong that only the action of

detergents

detergents can release the protein from the membrane

can release the protein from the membrane .

Thus, this enzyme is classified as an integral membrane

Thus, this enzyme is classified as an integral membrane

protein

protein , although it is not a membrane-spanning protein.

, although it is not a membrane-spanning protein.

The substrate for this enzyme

The substrate for this enzyme

, arachidonic

, arachidonic

acid

acid

, is a hydrophobic molecule generated by

, is a hydrophobic molecule generated by

the hydrolysis of membrane lipids.

the hydrolysis of membrane lipids.

Arachidonic

Arachidonic

acid reaches the active site

acid reaches the active site

of the enzyme from

of the enzyme from

the membrane without entering an aqueous

the membrane without entering an aqueous

environment by

environment by

traveling through

traveling through

a

a

hydrophobic

hydrophobic

channel in the protein

channel in the protein

drugs such as

drugs such as

aspirin and ibuprofen block the

aspirin and ibuprofen block the

channel

channel

and

and

prevent prostaglandin synthesis

prevent prostaglandin synthesis

by

by

inhibiting the cyclooxygenase activity of the

inhibiting the cyclooxygenase activity of the

synthase. In the case of aspirin, the drug acts

synthase. In the case of aspirin, the drug acts

through the

through the

transfer of an acetyl group from

transfer of an acetyl group from

the aspirin to a serine residu

the aspirin to a serine residu

e that lies along

e that lies along

the path to the active site

the path to the active site

Two important features emerge from our

Two important features emerge from our

examination of these three examples of

examination of these three examples of

membrane protein structure.

membrane protein structure.

First

First

, the parts

, the parts

of the

of the

protein that interact with the

protein that interact with the

hydrophobic parts of the membrane are coated

hydrophobic parts of the membrane are coated

with nonpolar amino acid side chains,

with nonpolar amino acid side chains,

whereas those parts that interact with the

whereas those parts that interact with the

aqueous environment are much more

aqueous environment are much more

hydrophilic.

hydrophilic.

Second

Second

, the

, the

structures

structures

positioned within the membrane are quite

positioned within the membrane are quite

regular and, in particular

regular and, in particular

, all backbone

, all backbone

hydrogen-bond donors and acceptors

hydrogen-bond donors and acceptors

participate in hydrogen bonds.

participate in hydrogen bonds.

Breaking a hydrogen bond within a membrane

Breaking a hydrogen bond within a membrane

is quite unfavorable, because little or no

is quite unfavorable, because little or no

water is present to compete for the polar

water is present to compete for the polar

groups.

groups.

Membrane Fluidity Is Controlled by Fatty Acid

Membrane Fluidity Is Controlled by Fatty Acid

Composition and Cholesterol Content

Composition and Cholesterol Content

transport or signal transduction

transport or signal transduction , depend on the

, depend on the

fluidity

fluidity of the membrane lipids

of the membrane lipids

The transition from the rigid to the fluid state occurs

The transition from the rigid to the fluid state occurs

rather abruptly as the temperature is raised above

rather abruptly as the temperature is raised above T

T

mm

the melting temperature.

the melting temperature. This transition temperature

This transition temperature

depends on the length of the fatty acyl chains and on

depends on the length of the fatty acyl chains and on

their degree of unsaturation

their degree of unsaturation

. saturated fatty acyl . saturated fatty acyl

residues favors the rigid state.

residues favors the rigid state.

On the other hand,

On the other hand, a cis double bond produces a bend in

a cis double bond produces a bend in

the hydrocarbon chain. This bend interferes with a

the hydrocarbon chain. This bend interferes with a

highly ordered packing of fatty acyl chains

highly ordered packing of fatty acyl chains , and so

, and so T

T

m

m

is lowered

is lowered .

As the temperature is

As the temperature is

raised , the

raised , the

phospholipid membrane

phospholipid membrane

changes from a packed

changes from a packed

, ordered state to a

, ordered state to a

more random one.

more random one.

Na K pump – read page 164

Na K pump – read page 164

Na

Na

+

+

-K

-K

+

+

pump

pump or the

or the Na

Na

+

+

-K

-K

+

+

ATPase

ATPase

. The hydrolysis of . The hydrolysis of

ATP by the pump provides the energy needed for the

ATP by the pump provides the energy needed for the

active transport of Na

active transport of Na

out of the cell and K

out of the cell and K

into

into

the cell, generating the gradient. The pump is

the cell, generating the gradient. The pump is

called the Na

called the Na

-K

-K

ATPase

ATPase because the hydrolysis of

because the hydrolysis of

ATP occurs only when Na

ATP occurs only when Na

and K

and K

are bound to the

are bound to the

pump. Moreover, this

pump. Moreover, this ATPase

ATPase , like all such enzymes,

, like all such enzymes,

requires Mg

requires Mg

2+

2+

. The active transport of Na . The active transport of Na

and K

and K

is

is

of great physiological significance. Indeed, more

of great physiological significance. Indeed, more

than a third of the ATP consumed by a resting

than a third of the ATP consumed by a resting

animal is used to pump these ions.

animal is used to pump these ions. The Na

The Na

-K

-K

gradient in animal cells controls cell volume,

gradient in animal cells controls cell volume,

renders neurons and muscle cells electrically

renders neurons and muscle cells electrically

excitable, and drives the active transport of

excitable, and drives the active transport of

sugars and amino acids.

sugars and amino acids.

Digitalis

Digitalis

, a mixture of

, a mixture of

cardiotonic steroids derived from

cardiotonic steroids derived from

the dried leaf of the foxglove

the dried leaf of the foxglove

plant (

plant (

Digitalis purpurea

Digitalis purpurea

), is of

), is of

great clinical significance.

great clinical significance.

Digitalis increases the force of

Digitalis increases the force of

contraction of heart muscle,

contraction of heart muscle,

which

which

makes it a choice drug in the

makes it a choice drug in the

treatment of congestive heart

treatment of congestive heart

failure

failure

. Inhibition of the Na

. Inhibition of the Na

++

-K

-K

++

pump by

pump by

digitalis leads

digitalis leads

to a higher level of

to a higher level of

Na

Na

inside the cell.

inside the cell.

The diminished Na

The diminished Na

gradient

gradient

results in slower extrusion of

results in slower extrusion of

Ca

Ca

2+2+

by the sodium—calcium

by the sodium—calcium

Multidrug

Multidrug Resistance and

Resistance and

Cystic Fibrosis

Cystic Fibrosis

Highlight a Family of Membrane

Highlight a Family of Membrane

Proteins with ATP-Binding

Proteins with ATP-Binding

Cassette Domain

Cassette Domain s

s

Tumor cells in culture often

Tumor cells in culture often

become resistant to drugs that

become resistant to drugs that

were initially quite toxic to

were initially quite toxic to

the cells.

the cells.

The development of resistance

The development of resistance

to one drug also makes the

to one drug also makes the

cells less sensitive to a

cells less sensitive to a

range of other compounds. This

range of other compounds. This

phenomenon is known as

phenomenon is known as

multidrug resistance

multidrug resistance .

Good example is a membrane

Good example is a membrane

protein called the

protein called the multidrug

multidrug

resistance protein (MDR)

resistance protein (MDR) or

or P-

P-

glycoprotein

glycoprotein (“glyco” because

(“glyco” because

it includes a carbohydrate

it includes a carbohydrate

moiety). Thus, when cells are

moiety). Thus, when cells are

A related protein was

A related protein was

discovered through studies

discovered through studies

of

of

cystic fibrosis

cystic fibrosis

The gene found to be mutated

The gene found to be mutated

in the affected persons

in the affected persons

encodes a protein, now

encodes a protein, now

called

called

cystic fibrosis

cystic fibrosis

transmembrane conductance

transmembrane conductance

regulator

regulator

(CFTR)

(CFTR)

. CFTR acts

. CFTR acts

as an ATP-regulated

as an ATP-regulated

chloride channel

chloride channel

in

in

the plasma membranes of

the plasma membranes of

epithelial cells. cystic

epithelial cells. cystic

fibrosis results from a

fibrosis results from a

decrease in fluid and salt

decrease in fluid and salt

secretion

secretion

by CFTR. As a

by CFTR. As a

consequence of this defect,

consequence of this defect,