CDC1348 lecture Krahn - Composition and structure of biological...
Transcript of CDC1348 lecture Krahn - Composition and structure of biological...
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Composition and structure of biological membranes, interaction of proteins with
membranes
Michael. P. KrahnMedical Cell Biology
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Cell membranes - functions
Michael Krahn Composition of cell membranes
Limitation
BarrierIons (Na+, K+, Cl-, Ca2+)Water, metabolites,…..Pathogens……
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Cell membrane – barrier function
Michael Krahn
Neurons: Excitation / action potential (Na+-influx depolarisation)
Cl- Na+
Cl- Na+
Cl-Na+
K+
K+
K+
K+Na+-channel
Cl- Na+
Cl- Na+
Cl-Na+
Cl- Na+
Cl- Na+
Cl-Na+
K+
K+
K+
K+
K+
K+
K+
K+
Na+
Na+
Na+
Na+Membrane potential
Animal cells ~ -70mV
Composition of cell membranes
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Cell membrane – functions
Michael Krahn
Limitation
BarrierIons (Na+, K+, Cl-, Ca2+)
Polarity & directed transport (luminal <> basal)
water, metabolites,…..
Signal transduction
pathogens……
Composition of cell membranes
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Cell membranes - Compartmentalization
Michael Krahn
Living room
Kitc
hen
office
corr
idor
WC
Composition of cell membranes
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Cell membrane – composition
Michael Krahn
Cyto-Plasma
PlasmamembranPlasmalemma
Composition of cell membranes
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Cell membrane – Lipid bilayer
Michael Krahn
“Amphipathic“
Hydrophilic head (polar or charded)
Lipophilic tail = fatty acid soluble(lipophilic, hydrophobic).
= water soluble (hydrophilic, lipophobic)
Micelle: hydrophobic centerMicelle: hydrophobic center
water
“Lipid monolayer“
Vesicel: hydrophilic centerVesicel: hydrophilic center
“Lipid bilayer“
energetically unfavorableenergetically unfavorable
Energetically favorableEnergetically favorable
LiposomeLiposome
Composition of cell membranes
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Cell mebrane – dimension
Michael Krahn
Erythrocyte
Basal invagination of a tublar cell in the kidney
5 nm
Composition of cell membranes
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Cell membrane – (Phospho)Lipids
Michael Krahn
Phospholipids
Hydrogentail
Glycerine
CholinePhosphate
Phosphoglycerides
Cell membranes: 500‐1000 different substances
Composition of cell membranes
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Cell membranes – (Phospho)Lipids
Michael Krahn
Sphingosine Sphingo‐myelin
Phosphatidyl‐Serine
Phosphatidyl‐ethanolamine
Phosphatidyl‐Choline
Hydrogen tail
Glycerine
Choline
Phosphate
PhosphoglyceridesSphingo‐lipids
50% Phospholipids (mammalian cells)
Composition of cell membranes
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Cell membrane – Asymmetry
Michael Krahn
cytoplasm
extracellular space
Phosphatidyl‐ethanolamins
Phosphatidyl‐Serins
Phosphatidyl‐Cholins
Sphingo‐myelin
Glykolipids‐
Composition of cell membranes
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Cell membrane – Dynamics
Michael Krahn
Lateral diffusion (very frequent) = 2µm/s
Flexion Rotation
Flip-Flop (rare)
Composition of cell membranes
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Cell membranes – stabilisation
Michael Krahn
Polar head group
Rigid region stabilized by Cholesterol
Region of increased fluidity
2. Cholesterol (~ 20%)(only in animal cells!!!)
1. Unsa urated FA↑ Fluidity↑
Hydrogentail
Glycerine
CholinePhosphate
rigid
3. Temperature(Bacteria/Yeast: Cold Unsa urated FA↑)
Composition of cell membranes
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Cell membrane – stabilisation
Michael Krahn
Bacteria
Plants
No steroids
No cholesterol, but other steroids
Cell wall
Plasma membrane
Cell wall
Plasma membrane
Composition of cell membranes
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Cell membranes – membrane proteins
Michael Krahn
Lipid bilayer
Integral membrane proteins 50%
50%
A wall without windows or doors is useless ……
Composition of cell membranes
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Cell membrane –Lipid rafts
Michael Krahn
Liposomes
Phosphatidylcholine : Sphingomyelin
1:1
Phosphatidylcholine : Sphingomyelin :
Cholesterol1:1:1
Atomic-Force-Microscopy
GPI-anchored proteintransmembran protein Lipid-Raft – functions:
- Endocytosis
- Protein-sorting
- Signal transduction
- ……
Composition of cell membranes
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Cell membranes - Phosphatidyl-inositols (PtdIns)
Michael Krahn
PO4
Phosphatidylinositol-4-phosphat (PtdIns-4P)
Phosphatidyl-inositol (PI)
PO4
Phosphatidylinositol-3,4-bi-phosphat (PtdIns(3,4)P2
Phosphatidylinositol-3,4,5-tri-phosphat (PtdIns(3,4,5)P3
Phosphatidylinositol-4,5-bi-phosphat (PtdIns(4,5)P2PO4PO4
PO4
Composition of cell membranes
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Cell membranes - Phosphatidyl-inositols (PtdIns)
Michael Krahn
Phosphatidyl-inositol (PI)
PtdIns-4P
PI4-Kinase PI4-Phophatase
PtdIns(4,5)P2
PI5-Kinase
PI5-Phosphatase
PtdIns(3,4,5)P3
SHIP1/2
PtdIns(3,4)P2
PI3-PhosphatasePI3-Kinase
PTENPI5-Kinase
PI3-Kinase
Composition of cell membranes
PtdIns-3PPI3-K
PtdIns(3,5)P2
PI3P-5K
PtdIns-5P
PI5-K
PI5P-4K
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Cell membranes - Phosphatidic-acid (PA)
Michael Krahn Composition of cell membranes
Hydrogentail
Glycerine
CholinePhosphate
Phosphatidyl choline
Hydrogentail
Glycerine
acidPhosphate
Phosphatidic acid
OH
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Phosphatidic acid - synthesis
Michael Krahn Composition of cell membranes
Hydrogentail
Glycerine
acidPhosphate
Phosphatidic acid
OH
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Phosphatidic acid – Three ways of synthesis
Michael Krahn Composition of cell membranes
Glycerine
acidPhosphate
Phosphatidic acid
OH
R R
Phosphatidyl cholinePhospho‐lipase D (PLD1/2)
Glycerine
acidPhosphate
1‐acyl‐sn‐glycerol‐phosphate = lysophosphatidic acid
OH
R OH
Glycerine
acidPhosphate
sn‐Gycerol‐3‐Phosphate
OH
OH OH
Acyl‐transferase I(GPAT1‐4)
Acyl‐Transferase II(LPAT1‐5)
Glycerol
(1,2)Diacyl glycerol (DAG)
OH
R R
DAG‐Kinase
timely & spatially regulated = signalling
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Phospholipids-distribution in (mammalian) cells
Michael Krahn Composition of cell membranes
Lemmons 2008
G. van Meer et al. 2008
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Phospholipids-distribution in (mammalian) cells
Michael Krahn Composition of cell membranes
Lemmons 2008Cinosi et al. 2011
Phosphatidylethanolamine ca. 15%Phosphatidylcholine ca. 30%
Sphingomyelin ca. 15%Cholesterol ca. 25%
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Phospholipids-distribution in (mammalian) cells
Michael Krahn Composition of cell membranes
Idevall‐Hagren and Camilli 2016
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Membrane targeting of proteins
Michael Krahn Composition of cell membranes
1. Transmembrane proteins
2. GPI-anchored proteins
3. Protein modifications: Lipid anchors- Farnesylation: CAAX- Palmitoylation: Cys- Myristoylation: M-Gly
4. Lipid-binding domains
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Phospholipid-binding domains
Michael Krahn Composition of cell membranes
Kahn and Lambright 2015
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Phospholipid-binding domains
Michael Krahn Composition of cell membranes
1. PH (Pleckstrin homology) domains (ca. 100aa, 285 in Hs):
- Pleckstrin- Phospholipase Cδ
- Akt (PKB) - PDK1- BTK- GRP1 (GEF for Arf6)
…..GEFs, GAPs, kinases
PtdIns(4,5)P2
PtdIns(3,4,5)P3
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Promiscuity of PH domains
Michael Krahn Composition of cell membranes
Bruntz 2014
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Phospholipid-binding domains
Michael Krahn Composition of cell membranes
3. FYVE domain (+ Zn2+):- endosomal proteins(e.g. EEA1, Vps27p/Hrs)
2. ENTH (Epsin N-terminal homology)- Epsin
PtdIns(4,5)P2
5. C1 domain (+ Zn2+):- PKCδ
DAG
4. PX domain:- Sorting nexins (Snx)
PtdIns-3P
6. C2 domain (+ Ca2+) :- PKCs- KIBRA
PtdSer
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Phospholipid-binding domains
Michael Krahn Composition of cell membranes
7. Annexin domain
8. BAR-domain- Sorting nexins- GAPs
9. F-BAR-domain- Syndapin
Acidic PhospholipidsSensingmembranecurvature
Stahelin 2009
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Phospholipid-binding domains
Michael Krahn Composition of cell membranes
Stahelin 2009
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Phospholipid-binding domains – Polybasic motifs
Michael Krahn Composition of cell membranes
Cox 2015
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Phospholipid-binding domains – Polybasic motifs
Michael Krahn Composition of cell membranes
Dogliotti et al. 2017
GFP-LKB1 DE-Cad DlgMerge +
DAPI
DrosophilaGFP-LKB1
Lysophosphatic acid
Lysophosphocholine
PtdInsPtdIns(3)P
PtdIns(4)P
PtdIns(5)PPhosphatidylethanolamine(PE)
Phosphatidylcholine (PC)
Sphingosine-1phosphate
PtdIns(3,4)P2
PtdIns(3,5)P2PtdIns(4,5)P2
PtdIns(3,4,5)P3
Phosphatidic acid (PA)Phosphatidylserine (PS)blank
LKB1 LKB1LB
GFP-LKB1LB DE-Cad DlgMerge + DAPI
DrosophilaGFP-LKB1LB
NH2 - - COOH
VKKKGSALKRRAKKLTSCISVRKLSHCRTS538 567
5671kinase domainDrosophila LKB1
LKB1
PA PIP2 PIP3
P L P L P L
LKB1∆LB
Liposomesflotation assay
GFP-LKB1LB Baz MirMerge + DAPI
GFP-LKB1 Baz MirMerge + DAPI
DrosophilaGFP-LKB1
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Phospholipid-binding domains – Polybasic motifs
Michael Krahn Composition of cell membranes
Krahn et al. 2010Kullmann and Krahn 2018
PDZ 1 PDZ 2 PDZ 3
1 1464
Par3
aPKC‐BD
P‐ Par1
P‐ Par1
SSRAKKPSILRGIGHMFRFGKNRKD
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Michael Krahn
Tight Junctions (TJ)
Adherens Junctions (AJ)
apical
basal
PtdIns(4,5)P2
PtdI
ns(3
,4,5
)P3
PtdIns(3,4,5)P3
PtdIns(4,5)P2
GFPGFP Green fluorescent proteinGFPGFP
Martin Belmonte….. and Keith Mostov 2007
Plekstrin-homology domain(Phospholipase Cδ)
Plekstrin-homology domain(Akt1)
GFPGFP
Phospholipids of the cell membrane as determinants of polarity
Composition of cell membranes
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Michael Krahn
Phospholipids of the cell membrane as determinants of polarity
Composition of cell membranes
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Michael Krahn
TJ
AJ
apical
basal
PtdIns(4,5)P2
PtdI
ns(3
,4,5
)P3
PtdIns(3,4,5)P3
PtdIns(4,5)P2
Martin Belmonte….. and Keith Mostov 2007
Ax2Ax2
Ax2Ax2 Annexin-2Cdc42Cdc42
aPKCaPKC
Cdc42Cdc42 Cdc42 (kleine GTPase)
aPKCaPKC Atypische Kinase C
Composition of cell membranes
Phospholipids of the cell membrane as determinants of polarity
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Michael Krahn
TJ
AJ
apical
basal
PtdIns(4,5)P2
PtdI
ns(3
,4,5
)P3
PtdIns(3,4,5)P3
PtdIns(4,5)P2
Ax2Ax2
Ax2Ax2 Annexin-2Cdc42Cdc42
aPKCaPKC
Cdc42Cdc42 Cdc42 (kleine GTPase)
aPKCaPKC Atypische Kinase C
Ax2Ax2
aPKCaPKC
Cdc42Cdc42
Composition of cell membranes
Phospholipids of the cell membrane as determinants of polarity
Martin Belmonte….. and Keith Mostov 2007
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Michael Krahn Composition of cell membranes
Phospholipids of the cell membrane as determinants of polarity
Martin Belmonte….. and Keith Mostov 2007
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Michael Krahn
TJ
AJ
apical
basal
PtdIns(4,5)P2
PtdI
ns(3
,4,5
)P3
PtdIns(3,4,5)P3
PtdIns(4,5)P2
Ax2Ax2
Cdc42Cdc42aPKCaPKC
aPKCaPKC atypical proteinkinase C
Microdomains of the plasma membrane as signaling hubs
aPKCaPKC
Kinase activity↑
aPKC(closed
conformation)
= inactive
aPKC(open
conformation)
= active
Composition of cell membranes
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Michael Krahn
TJ
AJ
apical
basal
PtdIns(4,5)P2
PtdI
ns(3
,4,5
)P3
PtdIns(3,4,5)P3
PtdIns(4,5)P2
Ax2Ax2
Cdc42Cdc42aPKCaPKC
PDK-1PDK-1
PDK-1PDK-1Phospho-inositol-dependentKinase
PTENPTEN
PI3-KPI3-K
PDK-1PDK-1AktAktP
Proteinsynthese ↑Zellwachstum ↑
Zellproliferation↑
PI3-KPI3-KPhospho-inositol-3-Kinase
PTENPTEN Phosphatase andtensin homolog
Tumor cells: PI3K↑PTEN↓
PI3-KPI3-K
Protein synthesis ↑Cell growth ↑
Cell proliferation↑
Composition of cell membranes
Microdomains of the plasma membrane as signaling hubs
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Michael Krahn Composition of cell membranes
Microdomains of the plasma membrane as signaling hubs
Kölsch et al. 2008
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AMPKAMPKP
AMP
LKB1LKB1
mTORP
P
PIP3PIP3
AktAktP
PLDPCPC
Balanced cell growth and proliferation
PAPA
Healthy tissue
PIP3PIP3
AktAktP P P
PCPCPLD
PAPA
AMPKAMPK
LKB1LKB1
Cell proliferationCell growth
Tumor progression
mTORP
P P
Tumor cells
Dogliotti et al., 2017Kullmann and Krahn 2018
Michael Krahn
PAPA Phosphatidic acid
PCPC Phosphatidylcholine
PLD Phospholipase D
Composition of cell membranes
Microdomains of the plasma membrane as signaling hubs
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Michael Krahn
Detection of Phospholipids
Composition of cell membranes
Hagren and Camilli 2016
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Michael Krahn
Manipulation of Phospholipids - Chemicals
Composition of cell membranes
Hagren and Camilli 2016
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Michael Krahn
Manipulation of Phospholipids - Optogenetics
Composition of cell membranes
Hagren and Camilli 2016