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Lipids, Membranes and Membrane Proteins|Graduate Biochemistry 7| Tulane

Overview

A cell is a membrane-rich environment

Classes of lipids

Structure of lipids

Polymorphic phase behavior of lipids

The lipid bilayer membrane

The fluid mosaic model of biological membranes

Classes and functions of membrane proteins

Folding and structure of membrane proteins

Hydropathy plots

A cell is a membrane-rich environment

Classes of Lipids

Fatty acid (e.g. palmitate, oleate)
Energy storage metabolite
Building block of other lipids

Triacylglycerols (fat)

Energy storage

Glycerophospholipids
Form lipid bilayer membrane
Signal transduction

Sphingolipids
Form lipid bilayer membranes
Signal transduction

Steroids
Rigidify membranes (Cholesterol)
Membrane-crossing hormones (e.g. Estrogen)

Fatty Acids - structure and nomenclature

Fatty acid rules of nomenclature

Carbon numbering start at carboxyl carbon

Double bonds are numbered at the first carbon

cis configuration is normal (trans is specified)

Syntax for nomenclature
length:#double bonds (list of double bond locations)

16:0 = palmitic acid
18:1(9) = oleic acid (sometimes written 18:1(Δ9))
20:4(5,8,11,14) = arachidonic acid

palmitic acid	oleic acid	arachidonic acid

	© PubChem ID= 985, 445639, 444899

Typical eukaryotic fatty acid structure

Even number of carbons

Non-conjugated double bonds (double bonds are separated by at least one CH2)
Double bonds are normally cis If a double
bond is trans it is specified in the name

PS:
Even number: Synthesis and degraded of the fatty acid are occur two carbons at a time.
Conjugated double bounds: Conjugated double bounds could make fluorescence. Exp: Retinol, or vitamin A, has five conjugated double bonds and absorbs the violet part of the spectrum, thus appearing as yellow.^[1]
Cis: As the picture above, the hydrogen atoms are on the same side.

Palmitic acid
Oleic acid

Classes of diacyl lipids

The two backbone molecules in diacyl lipids:

Glycerol (Glycerophospholipids)
Serine (Sphingolipids)

Diacyl lipids are the main structural component of bilayers and are the ONLY component that will form bilayers in pure form.

Be able to draw the base of this two lipids.

Glycerol	Serine

Two fatty acids connect to two hydroxyl groups independently, the rest hydroxyl group connect to the phosphate acid which could connect the variety head.	Two fatty acids connect to Amino group and carboxyl group. R chain connect variety heads

Variety of Glycerophospholipid (head)



Phosphatidic acid	Phosphatidylethanolamine	Phosphatidylcholine

Phosphatidylglycerol	Phosphatidylserine	Phosphatidylinositol
	© PmdChem

second messenger molecule

Often phosphorylated on one o
several hydroxyls

No head


© PubChem ID=6026790

A signaling molecule

Phosphatidic acid: is rare in memebrane but it’s intermediate of the metabolic.
Phosphatidylcholine: Most abundant glycerophospholipid found in eukaryotic membrane. Innert, not strong interaction with others. (Outside of the membrane)
Phosphatidylethanolamine: Charge and much activity than Phosphatidylcholine, inside the cell.
Phosphatidylglycerol: also abundant in prokaryotic cell.
Phosphatidylserine: active, inside the cell. Common in eukaryotic cell. It’s not a sugar group, it is a sample carbon base ring.
Phosphatidylinositol: Negative Charged, signaling molecule. Second messenger.

Sphingolipid Headgroups

Sphingomyelin


Sphingomyelin	Phosphocholine group

Cerebrosides

Simple sugars

Galactose, lactose, glucose (uncharged)

Cerebrosides

Gangliosides

More complex carbohydrates
(anionic) Found in brain

Ganglioside GM1

Fatty acid melting points

The longer the chain, the higher the melting point.
The more double bounds, the lower the melting point.


© PubChem ID= 3018404
Melting point:82-95 °C.


© PubChem ID= 5280450
Melting point:-9 °C.

PS: Cells control the fluid of the membrane by change the type of lipid (melting point) to achieve specific biology purpose.

Four common fatty acid you should remember

Symbol	Common name	Systematic name	Structure	mp (°C)
14:0	Myristic Acid	Tetradecanoic acid	CH₃(CH₂)₁₂COOH	52
16:0	Palmitic acid	Hexadecanoic acid	CH₃(CH₂)₁₄COOH	63.1
20:0	Arachidic acid	Eicosanoic acid	CH₃(CH₂)₁₈COOH	75.4
24:0	Lignoceric acid	Tetracosanoic acid	CH₃(CH₂)₂₂COOH	84.2

Phospholipases and cyclooxygenases


© Konstantin Balashev

Phospholipases A₁, A₂, B, C, and D.
Most phospholipids was cleaved by Phospholipase A₂

cyclooxygenases


© NV Chandrasekharan

Cyclooxygenases (COXs) catalyze the rate-limiting step in the production of prostaglandins, which is an signal molecule and both soluble in water and lipids.

Cholesterol and other steroids


© PubChem ID= 5997

Cholesterol is a component of biological membranes

Up to 50% of a membrane’s lipid can be cholesterol

It rigidifies or stiffens bilayers

Cholesterol is converted to bile acids (used in digestion) and steroid hormones (used for signaling)

Steroid hormones freely cross membranes and act directly on nuclear receptors

The hydroxyl group of the cholesterol makes it float on the cell membrane.
In the RBC, the cholesterol in cytomembrane could up to 50% and which makes the membrane very rigidity. (try to keep it’s shape when it through the catepillars) Lake of most membrane proteins. As a contrast, the mitochondria’s membrane does not have cholesterol and has very high fluidity which needs to go constant conformation change. One of the fluidity membrane we know are rod and cone cell which are light recept cells. They need to interact quickly. As a result, they are made highly portion of the saturated fatty acids and very little of cholesterol.

Steroid Hormones	© PubChem

These hormones are both soluble in water and lipids. So they can pass membrane easily.

Polymorphic Phase Behavior of Lipids

All lipids spontaneously separate from water

The form of the lipid phase depends on the molecular “shape” of the molecule

Head group end

Molecular shap hypothesis:

Lipid Type	Composition	Types in below
Fatty acid Other detergents	micelle	Type 1
Diacyl Lipid	bilayer	Type 0
Diacyl Glycerol	inverse micelle	Type 2

Core of the membrane is the most hydrophobic environment we can find.
In the core of folded protein, the hydrophobic core coudl have a few polar groups. But not poler group in Membrane core. Which gaves the membrane a barrier property


© Chandrashekhar V. Kulkarni

“Fluid Mosaic” model of biological membranes


© Veronika Novotná, et al.

Living cells actively maintain a certain membrane fluidity by adjusting the composition of the lipids in their membranes.

The lipids are the solvents, the proteins are solutes.
This drawing is wrong. The membrane can pack more protein than it. Exp: Mitochondria.

Secondary Structure Types in Membranes


© Guangshun Wang

Header One	Header Two
Water
Interface	15 Å
Core	30 Å
Interface	15 Å
Water

Membrane-spanning proteins have very few polar groups groups, such as the peptide back bone exposed to the core of the bilayer.

Membrane Protein
α-helix	19-25 residues to span the membrane Self hydrogen-bonding Mostly hydrophobic along the membrane-spanning segment About 25% of ALL proteins are helical membrane proteins
β-barrel	8-12 residues are required to span membrane Not self Hydrogen bonding Dyad repeat motif (alternating hydrophobic/hydrophilic) Found in the outer membranes of some bacteria and in mitochondria

Membrane integral protein challenges:

Residues: Hydrophobic residues on the menbrane core area
Carbon back-bond: Form hydrogen bond with itself.

Typically, the surface of the proteins interacted with membrane are even more hydroponically than the core of folded protein.

30Å membrane core takes about 20 residues of α-helix.
β-barrel only find in gram-negative bacterial, mitochondrial and chloroplasts. (Human, about 50 β-barrel gene and only on mitochondria genome. 2% of gene is β-barrel in E. coli)

Structure of Bovine Rhodopsin

A protin in eye cell membrane.
Salt bridges and hydrogen bonds are rare in membrane protein.


© Molview, PDBID=1f88 Rhodopsin Dimer

Structure of Rhodopsin
Spacefilling

Side View Top View

Structural features of membrane proteins

Exterior is very hydrophobic over ~30 Å slab of the membrane

Interior has amino acid composition like that of a soluble protein

Helices are close-packed

Salt-bridges and helix-helix hydrogen bonds are rare

ionizable residues are nearly always salt bridged.

Helix-helix interactions are mainly driven by van der Waals packing


© Yi Xia

The human erythrocyte protein Glycophorin A has a single membrane-spanning α-helix

Hydropathy Analysis


© Yair Benita, et al.

Take the 19 amino acids in a box from the chain and calculate the hydrophobicity, and them you slid it one by one to make the Sliding Window Hydropathy Plot.