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VAP-B and its role in Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS)
No cure or effective treatment
Rapidly progressive neurodegenerative disorder characterized by death of
motor neurons in the cerebral cortex, brain stem, and spinal cord.
Two forms :Sporadic (~90%), Familial (10%)- 20% of familial cases are caused
by dominantly inherited mutations in SOD1
Prevalence of 4-6 per 100,000 population, and an average mortality of 5 years
after onset.
Most studies on the familial form have been focused on SOD1
A complex interplay between multiple pathogenic processes including,
Oxidative Stress,
Protein Aggregation,
Mitochondrial Dysfunction excitotoxicity,
Impaired Axonal Transport
1251 5942 211158 243220
VAPB-1 H. sapiens LSTR-LLALVVLFFIVGVIIGKIAL
aVAP33 A.californica VRAFPPVVYVVAAIILGLIIGKFLL
DVAP33A D. melanogaster QIPVFYIAVAIAAAIVSLLLGKFFL
VAP homolog C.elegans YPTLQIFLIAVAALLIGLIVGRLF-
VAP27-1c A.thaliana IPFMYVLLVGLIGLILGYIMKRT--
SCS2 S.cerevisiae SSMGIFILVALLILVLGWFYR----
VAP homolog D.discoideum FNHYQTLIVIFAIAILSFIFGKLI-
CCDMSP Domain
VAP
consensus
sequence
VAPB-1 H. sapiens FKVKTTAP--YCVRPNSG
aVAP33 A. californica FKVKTTAP--YCVRPNSG
DVAP33A D. melanogaster FKIKTTAP--YCVRPNIG
VAP-homolog C. elegans FKVKTTAP--YCVRPNSG
VAP27-1c A. thaliana FKVKTTNP--YCVRPNTG
SCS2 S. cerevisiae FKVKTTAP--YCVRPNAA
VAP-homolog D. discoideum FKVKTTAP--YCVRPNTG
MSP78 C. elegans YGIKTTNM--LGVDPPCG
VAPs-MSP homology * **** * * *
TMD
The P56S mutation in VAP-B causes motor neuron degeneration diseases
GXXXG
P56S
The P56S mutation induces cis to trans isomerization
The underlying mechanism of VAP-B(P56S)-induced ALSThe underlying mechanism of VAP-B(P56S)-induced ALS
The P56S mutation induces the formation of insoluble protein aggregates
Triton X-100 RIPA
β-tubulin
VAP-B
S P
P56S
S P S P S P S P S P S P
P56S P56SWTWT- -
IP:
VAP-B
P56S
W
T
P56S
W
T
Blot:
anti-Myc anti-Myc
anti-Myc FK2
IgG(LC)
IgG(HC)
The VAP-B(P56S) is polyubiquitinated
Wild-type VAP-B is recruited into VAP-B(P56S) aggregates S SP P
HA-VAP-B(WT)
Myc-VAP-B(P56S)
VAP-B: P56SWT
Potential mechanisms underlying the diseasePotential mechanisms underlying the disease
The disease is inherited in an autosomal dominant fashion
Loss of function Gain of toxic of function
WT WTWTP56SP56SP56S P56SP56SP56SP56S
UPR associated activity
Misfolded
conformation
P56SP56SP56SP56S
ub ub
ub
Proteasomal
dysfunction
ERAD ER Stress
Motor Neuron
Degeneration
Motor Neuron
Degeneration
P56SP56SWT WT WTP56S
Impaired lipid homeostasis
& membrane trafficking
FFAT
Structural requirements for VAP-B oligomerization and their contribution for
VAP-B(P56S) aggregation and neurotoxicity
Structural requirements for VAP-B oligomerization and their contribution for
VAP-B(P56S) aggregation and neurotoxicity
VAP-B (WT)MSP CC
GXXXG mutant (II)MSP CC
169
112
92
67
59
36.5
31
Monomer
Dimer
Tetramer
VAP-B(WT)VAP-B(I)VAP-B(II)K87/M89D
K87/M89D/(I)K87/M89D/(II)
YFP-TMD(II)
YFP-TMDYFP
YFP
Monomer
Dimer
169
112
92
67
59
36.5
31
YFP-TMD: WT II WT II
CL CL-Rev.
The GXXXG motif
VAP-B-∆MSPCC
CC VAP-B-∆MSP (II)
∆MSP-Myc: WT II WT II
CL CL-Rev.
Dimer
Monomer
MSP Dimer
Monomer
MSP-Myc:
CL
WT DD P56S
CL-Rev.
WT DD P56S
59
36.5
31
VAP-B-∆CCMSP
VAP-B-∆CC (II)MSP
The Coiled-coil domain
Monomer
Monomer*
Dimer
CL
Dimer*
CL-Rev.
∆CC/II
∆CC
II
W
T
∆CC/II
∆CC
II
W
T
P56S/∆CC
∆CC
P56S
W
T
P56S/∆CC/II
∆CC/II
II
P56S/II
Monomer*
Monomer
Dimer
Dimer*
The MSP domain
The P56S induces conformational changes of the MSP domain
Evidence: Mutation induces a ~18% increase in
the average diameter size of the domain
Suggests: Decrease in overall compactness
Evidence: The mutant rests essentially in an agglomerate
conformation at physiologic temperature!!
Suggests: Patologic propensity to aggregate
Evidence: Mutation induces secondary
Structure alterations
Suggests: Folding modifications
Evidence: Mutation induces exposure of hydrophobic patches
Suggests: Hydrophobic core destabilization
Evidence: ANS binding is decreased in VAP-P56S after incubation at 37ºC
Suggests: P56S mutants can clump together, likely involving
hydrophobic interactions, thus resulting in less available binding sites for
ANS. This may indicate that hydrophobic interactions are involved in the
formation of the agglomerates.
+VAP-B(P56S)-HA
WT
S P S P S P S P
∆CC∆CC/IIIIVAP-B-Myc:
IB: anti-HA
IB: anti-Myc
IB: anti-Myc
VAP-B
S P S P S P
VAP-B: WT P56S
Nir2
CERT
M
SP(P56S)
M
SP(W
T)
P56S/∆CC/II
M
ock
M
SP(87/89D)
+Nir2-HA
IB:anti-HA
IB:anti-HA
IB:anti-Myc
Lysate
IP:anti-Myc
The P56S mutation per se has no effect on FFAT binding.
Rather, it enhances VAP-B(P56S) oligomerization thereby
preventing FFAT binding.
The P56S mutation per se has no effect on FFAT binding.
Rather, it enhances VAP-B(P56S) oligomerization thereby
preventing FFAT binding.
The effect of the P56S mutation on FFAT binding
P56S insoluble aggregates
P56S Neurotoxicity
FFAT
FFATFFAT
MSP
Formation of insoluble protein aggregates by the P56S mutation
P56S
P56SP56S P56SP56S
P56SP56S
MSP MSP
P56SP56S
P56SP56S
Insoluble Aggregates
Amir Kedan
M.Sc. student
Omer Keinan
Ph.D. student
Orly Laufman
Ph.D. student
Acknowledgment
Koret Hischberg -Tel-Aviv University
Zvulun Elazar-Weizmann Institute
Tony Futerman-Weizmann Institute
Moti Liscovitch -Weizmann Institute
Chaya Brodie- Bar-Ilan University
Sean Munro-MRC, Cambridge, UK
Kentaro Hanada-Tokyo, Japan
Antonella De Matteis- Mario Negri, Italy
Michael Selitrennik
Research associate
So Hui Kim
Ph.D. student
Dr. Diego Peretti
Postdoctoral fellow
Dr. Cláudio M. Gomes
Dr. Sónia S. Leal
Collaboration
Tecnologia Química e Biológica (ITQB),
University Nova, Lisboa, Portugal
Former
Roy Amarilio
Sreekumar Ramachandran
Vladimir Litvak
Nili Dahan
Donghua Tian
Weizmann Institute of Science
Visit us…

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Sima Lev: VAP-B and its role in Amyotrophic lateral sclerosis

  • 1. VAP-B and its role in Amyotrophic lateral sclerosis
  • 2. Amyotrophic lateral sclerosis (ALS) No cure or effective treatment Rapidly progressive neurodegenerative disorder characterized by death of motor neurons in the cerebral cortex, brain stem, and spinal cord. Two forms :Sporadic (~90%), Familial (10%)- 20% of familial cases are caused by dominantly inherited mutations in SOD1 Prevalence of 4-6 per 100,000 population, and an average mortality of 5 years after onset. Most studies on the familial form have been focused on SOD1 A complex interplay between multiple pathogenic processes including, Oxidative Stress, Protein Aggregation, Mitochondrial Dysfunction excitotoxicity, Impaired Axonal Transport
  • 3. 1251 5942 211158 243220 VAPB-1 H. sapiens LSTR-LLALVVLFFIVGVIIGKIAL aVAP33 A.californica VRAFPPVVYVVAAIILGLIIGKFLL DVAP33A D. melanogaster QIPVFYIAVAIAAAIVSLLLGKFFL VAP homolog C.elegans YPTLQIFLIAVAALLIGLIVGRLF- VAP27-1c A.thaliana IPFMYVLLVGLIGLILGYIMKRT-- SCS2 S.cerevisiae SSMGIFILVALLILVLGWFYR---- VAP homolog D.discoideum FNHYQTLIVIFAIAILSFIFGKLI- CCDMSP Domain VAP consensus sequence VAPB-1 H. sapiens FKVKTTAP--YCVRPNSG aVAP33 A. californica FKVKTTAP--YCVRPNSG DVAP33A D. melanogaster FKIKTTAP--YCVRPNIG VAP-homolog C. elegans FKVKTTAP--YCVRPNSG VAP27-1c A. thaliana FKVKTTNP--YCVRPNTG SCS2 S. cerevisiae FKVKTTAP--YCVRPNAA VAP-homolog D. discoideum FKVKTTAP--YCVRPNTG MSP78 C. elegans YGIKTTNM--LGVDPPCG VAPs-MSP homology * **** * * * TMD The P56S mutation in VAP-B causes motor neuron degeneration diseases GXXXG P56S The P56S mutation induces cis to trans isomerization
  • 4. The underlying mechanism of VAP-B(P56S)-induced ALSThe underlying mechanism of VAP-B(P56S)-induced ALS The P56S mutation induces the formation of insoluble protein aggregates Triton X-100 RIPA β-tubulin VAP-B S P P56S S P S P S P S P S P S P P56S P56SWTWT- - IP: VAP-B P56S W T P56S W T Blot: anti-Myc anti-Myc anti-Myc FK2 IgG(LC) IgG(HC) The VAP-B(P56S) is polyubiquitinated
  • 5. Wild-type VAP-B is recruited into VAP-B(P56S) aggregates S SP P HA-VAP-B(WT) Myc-VAP-B(P56S) VAP-B: P56SWT Potential mechanisms underlying the diseasePotential mechanisms underlying the disease The disease is inherited in an autosomal dominant fashion Loss of function Gain of toxic of function WT WTWTP56SP56SP56S P56SP56SP56SP56S UPR associated activity Misfolded conformation P56SP56SP56SP56S ub ub ub Proteasomal dysfunction ERAD ER Stress Motor Neuron Degeneration Motor Neuron Degeneration P56SP56SWT WT WTP56S Impaired lipid homeostasis & membrane trafficking FFAT
  • 6. Structural requirements for VAP-B oligomerization and their contribution for VAP-B(P56S) aggregation and neurotoxicity Structural requirements for VAP-B oligomerization and their contribution for VAP-B(P56S) aggregation and neurotoxicity VAP-B (WT)MSP CC GXXXG mutant (II)MSP CC 169 112 92 67 59 36.5 31 Monomer Dimer Tetramer VAP-B(WT)VAP-B(I)VAP-B(II)K87/M89D K87/M89D/(I)K87/M89D/(II) YFP-TMD(II) YFP-TMDYFP YFP Monomer Dimer 169 112 92 67 59 36.5 31 YFP-TMD: WT II WT II CL CL-Rev. The GXXXG motif
  • 7. VAP-B-∆MSPCC CC VAP-B-∆MSP (II) ∆MSP-Myc: WT II WT II CL CL-Rev. Dimer Monomer MSP Dimer Monomer MSP-Myc: CL WT DD P56S CL-Rev. WT DD P56S 59 36.5 31 VAP-B-∆CCMSP VAP-B-∆CC (II)MSP The Coiled-coil domain Monomer Monomer* Dimer CL Dimer* CL-Rev. ∆CC/II ∆CC II W T ∆CC/II ∆CC II W T P56S/∆CC ∆CC P56S W T P56S/∆CC/II ∆CC/II II P56S/II Monomer* Monomer Dimer Dimer* The MSP domain
  • 8. The P56S induces conformational changes of the MSP domain Evidence: Mutation induces a ~18% increase in the average diameter size of the domain Suggests: Decrease in overall compactness Evidence: The mutant rests essentially in an agglomerate conformation at physiologic temperature!! Suggests: Patologic propensity to aggregate Evidence: Mutation induces secondary Structure alterations Suggests: Folding modifications
  • 9. Evidence: Mutation induces exposure of hydrophobic patches Suggests: Hydrophobic core destabilization Evidence: ANS binding is decreased in VAP-P56S after incubation at 37ºC Suggests: P56S mutants can clump together, likely involving hydrophobic interactions, thus resulting in less available binding sites for ANS. This may indicate that hydrophobic interactions are involved in the formation of the agglomerates.
  • 10. +VAP-B(P56S)-HA WT S P S P S P S P ∆CC∆CC/IIIIVAP-B-Myc: IB: anti-HA IB: anti-Myc IB: anti-Myc VAP-B S P S P S P VAP-B: WT P56S Nir2 CERT M SP(P56S) M SP(W T) P56S/∆CC/II M ock M SP(87/89D) +Nir2-HA IB:anti-HA IB:anti-HA IB:anti-Myc Lysate IP:anti-Myc The P56S mutation per se has no effect on FFAT binding. Rather, it enhances VAP-B(P56S) oligomerization thereby preventing FFAT binding. The P56S mutation per se has no effect on FFAT binding. Rather, it enhances VAP-B(P56S) oligomerization thereby preventing FFAT binding. The effect of the P56S mutation on FFAT binding
  • 13. FFAT FFATFFAT MSP Formation of insoluble protein aggregates by the P56S mutation P56S P56SP56S P56SP56S P56SP56S MSP MSP P56SP56S P56SP56S Insoluble Aggregates
  • 14. Amir Kedan M.Sc. student Omer Keinan Ph.D. student Orly Laufman Ph.D. student Acknowledgment Koret Hischberg -Tel-Aviv University Zvulun Elazar-Weizmann Institute Tony Futerman-Weizmann Institute Moti Liscovitch -Weizmann Institute Chaya Brodie- Bar-Ilan University Sean Munro-MRC, Cambridge, UK Kentaro Hanada-Tokyo, Japan Antonella De Matteis- Mario Negri, Italy Michael Selitrennik Research associate So Hui Kim Ph.D. student Dr. Diego Peretti Postdoctoral fellow Dr. Cláudio M. Gomes Dr. Sónia S. Leal Collaboration Tecnologia Química e Biológica (ITQB), University Nova, Lisboa, Portugal Former Roy Amarilio Sreekumar Ramachandran Vladimir Litvak Nili Dahan Donghua Tian
  • 15. Weizmann Institute of Science Visit us…