a new approach towards deciphering the protein code: the protein assembly model
DESCRIPTION
A new approach towards deciphering the protein code: The protein assembly model. Claire Lesieur [email protected]. Membrane (Lipids). Proteins. Nucleus (chromosome). Elements of the living world. Protein. Nucleus. Lipids. DNA. CHON. Chromosome. Protein Biological activities. - PowerPoint PPT PresentationTRANSCRIPT
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Claire [email protected]
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NucleusNucleus ProteinProtein
LipidsLipids
ChromosomeChromosome
DNADNA
NucleusNucleus(chromosome)(chromosome)
Membrane (Lipids)Membrane (Lipids)
ProteinsProteins
CHONCHON
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- CuttingCutting- RecognitionRecognition- EnzymeEnzyme- SignalingSignaling- CarrierCarrier- Shape generatorShape generator- Road networksRoad networks
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Function Shape How the shape provides a particular
function How the shape is acquired
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GKKHDGATTYQWGKKHDGATTYQW
????
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How it folds: Mechanisms of protein folding
How the information is encrypted in the sequences: CODING problem
ADRTGGILLKMHGGARECVVP
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All the information necessary for the protein folding is All the information necessary for the protein folding is within the protein primary sequencewithin the protein primary sequence
C.B. Anfinsen, Haber, E., Sela, M. & White, F. H. , Proc. C.B. Anfinsen, Haber, E., Sela, M. & White, F. H. , Proc. Nati. Acad. Sci. USA 47 (1961) 1309-1314.Nati. Acad. Sci. USA 47 (1961) 1309-1314.
Levinthal’s paradox(1968): not random search but directedLevinthal’s paradox(1968): not random search but directed
Levinthal, C. (1968) J. Chim. Phys. 65, 44-45.Levinthal, C. (1968) J. Chim. Phys. 65, 44-45.
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Short range interactionStructure TertiaireStructure Tertiaire
COOHCOOH
HH22NNmsms s-hourss-hours
Structure primaireStructure primaire Structure SecondaireStructure Secondairelong-rangelong-rangeinteractionsinteractions
short-rangeshort-rangeinteractionsinteractions
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X-ray crystallography + NMR: PDBX-ray crystallography + NMR: PDB
3D modeling: PDB3D modeling: PDB
~ 70 % Sequence similarity: 3D modeling~ 70 % Sequence similarity: 3D modeling
70 % similarity: different shape70 % similarity: different shape
Low sequence similarity: similar shapeLow sequence similarity: similar shape
Amino acids on the surface of proteins: Amino acids on the surface of proteins: changeablechangeable
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-strands transmembrane domain: 1010101-strands transmembrane domain: 1010101-helice transmembrane domain: 11111111111111111-helice transmembrane domain: 11111111111111111
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Geometrical constrain
Chemical constrain
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Domains Shape and role
??Sequence Pattern
Sequence PatternSequence Pattern
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Trends in Microbiology (2000). Vol 8 (4):169-172Trends in Microbiology (2000). Vol 8 (4):169-172
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Cholera toxinCholera toxin
• ABAB5 5 toxintoxin– A catalytic subunitA catalytic subunit– B receptor binding subunitB receptor binding subunit
• GMGM11: cell receptor: cell receptor• Endocytosed and traffic to the Endocytosed and traffic to the
ERER• ADP ribosylation of GADP ribosylation of G subunit subunit• Increase of cAMP leading to Increase of cAMP leading to
water losswater loss
CtxBCtxB55
CtxACtxA
ERER
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Assembly in vitroAssembly in vitro
PentamerePentamere
MonomereMonomere
pH 1pH 1
15 min15 min
pH 7pH 7
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-1,2 10-1,2 1066-1 10-1 10
66-8 10-8 10
55-6 10-6 10
55-4 10-4 10
55-2 10-2 10
5500
2 102 1055
200200 210210 220220 230230 240240 250250
pH 1pH 1
pH 7pH 7
NativeNative
Wavelength (nm)Wavelength (nm)
Mea
n r
esid
ue
Mo
lecu
lar
Ell
ipti
city
Mea
n r
esid
ue
Mo
lecu
lar
Ell
ipti
city
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Trp-fluorescence
Flu
ore
scen
ce I
nte
nsi
tyF
luo
resc
ence
In
ten
sity
320 340 360 3800
100
200
300
unfoldedunfolded
Wavelength (nm)
0
50
100
150
200
250
300
350
0 20 40 60
Time (min)Time (min)
exex= 295 nm= 295 nm
emem=352 nm=352 nm
Flu
ore
scen
ce I
nte
nsi
ty (
a.u
.)F
luo
resc
ence
In
ten
sity
(a.
u.)
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His
0
20
40
60
80
100
4,5 5 5,5 6 6,5 7 7,5 8
pHpH
CtxBCtxBF
un
ctio
nF
un
ctio
n
HISTIDINEHISTIDINE
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…
…CtxB5CtxB5
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Heat labile enterotoxin BHeat labile enterotoxin B Cholera toxin BCholera toxin B
LTBLTB CtxBCtxB
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N-terminal
0
20
40
60
80
100
4,5 5 5,5 6 6,5 7 7,5 8
pHpH
LTBLTBCtxBCtxB
Fu
nct
ion
Fu
nct
ion
N-terminalN-terminal
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LTB5LTB5
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Kinetics differences
On pathway intermediates differences
It is particular amino acids that are responsible for each individual step of assembly and folding
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Alzheimer, Parkinson, Prion diseases
Protein X: FOLD state: healthyProtein X: FOLD state: healthy
(Protein X)n: Assembly state: Lethal(Protein X)n: Assembly state: Lethal
Information for interfacesInformation for interfaces
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Protein Interface formation
Rules? Mechanism?
Preferential geometries related to preferential sequences of amino acids?
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INTERFACES:Zone de contact entre monomeres voisins
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Interface Trimer pentamer heptamer
Brin 1
Brin 2
0101 0101 Ch111Ch
n.a. Ch111Ch 1111/1
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Fibritin like domain
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Nombre de monomerNombre de monomer 2 3 4 5 6 7 8 9 10 11 12 2 3 4 5 6 7 8 9 10 11 12
Nombre de casNombre de cas 5722 1035 2340 168 721 46 512 45 87 8 2055722 1035 2340 168 721 46 512 45 87 8 205
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513 -524 LMITTECMVTDL aaa-bbbbbbb-
35-49GRNVVLDKSFGAPTI--bbbb-------bb
Monomer M
Monomer M+ 1
Distances
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5 97
1 92
2 525
177 367
1 194
4 233
96 336
2 526
6 523
64 549
3 97
1 94
344 471
8 80
5 111
10 88
1 302HY6 (30)
1N9R (68) 19 86
1WNR (94)
1JBM (78)
2F86 (129)
1G31 (107)
1LNX (74)
1Q57 (483)
2RAQ (94)
1GRL (518)
1IOK (524)
1PZN (240)
1J2P (229)
1Y7O(194)
2F6I (189)
1TG6 (193) 1 193
2CBY (179) 15 194
1OEL (525)
1LEP (92)
3BDU (51) 2 53
1HX5 (92)
betaalpharc
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3BDU 20-29, 38-533BDU 20-29, 38-53
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3BDU 1--111011-110110--103BDU 1--111011-110110--101G31 0--1-1001-100100--001G31 0--1-1001-100100--001JBM 110010001011001011011JBM 110010001011001011011LNX 1--0100010110000---11LNX 1--0100010110000---11N9R 0--0100011110010--111N9R 0--0100011110010--111J2P ----1000101100101--11J2P ----1000101100101--11HX5 ------0011110010--111HX5 ------0011110010--111LEP 0---10001000--00--111LEP 0---10001000--00--11Con2 ----1-001-1100-0-Con2 ----1-001-1100-0-
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1LEP: 1-8, 88-94, 40-57
1WNR: 1-8, 88-94, 44-57, 62-77
1HX5: 5-11, 94-97, 51-62, 68-80, 27-30
1G31: 8-15, 104-111, 68-85
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yeast
P. aerophilum: bacterium
Methanobacterium Thermautriophicum: extremophile
1N9R
1LNX
1JBM
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1JBM: 12-18, 42-50, 64-83
1LNX: 10-15, 25-32, 40-48, 63-77
1N9R: 66-82yeast
P. AerophilumHyperthermophilic bacterium
Methanobacterium Thermautriophicum: extremophile
1
1 + 1
1 +1 +1
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2CBY2CBY
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Geometry and function related
Family of protein interfaces
Assembly keys
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Classification of protein interfaces: Database
Systematic analysis of protein interfaces-subjective classification
Mathematical approach: Laurent Vuillon (LAMA)
Functional analysis of protein interfaces Protein Assembly mechanism from block:
Giovanni Feverati Stoechiometry/Symmetry: Paul Sorba Experimental tests: Claire Lesieur
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Alicia Ng Ling
Mun Keat Chong Boon Leng Chua Danyang Kong
Giovanni Feverati Paul Sorba