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Clifton, L. A., Wacklin-Knecht, H. P., Ådén, J., Ul Mushtaq, A., Sparrman, T. & Gröbner, G. (2023). Creation of distinctive Bax-lipid complexes at mitochondrial membrane surfaces drives pore formation to initiate apoptosis. Paper presented at 2023/06/07. Science Advances, 9(22), Article ID eadg7940.
Åpne denne publikasjonen i ny fane eller vindu >>Creation of distinctive Bax-lipid complexes at mitochondrial membrane surfaces drives pore formation to initiate apoptosis
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2023 (engelsk)Inngår i: Science Advances, E-ISSN 2375-2548, Vol. 9, nr 22, artikkel-id eadg7940Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Apotosis is an essential process tightly regulated by the Bcl-2 protein family where proapoptotic Bax triggers cell death by perforating the mitochondrial outer membrane. Although intensively studied, the molecular mechanism by which these proteins create apoptotic pores remains elusive. Here, we show that Bax creates pores by extracting lipids from outer mitochondrial membrane mimics by formation of Bax/lipid clusters that are deposited on the membrane surface. Time-resolved neutron reflectometry and Fourier transform infrared spectroscopy revealed two kinetically distinct phases in the pore formation process, both of which were critically dependent on cardiolipin levels. The initially fast adsorption of Bax on the mitochondrial membrane surface is followed by a slower formation of pores and Bax-lipid clusters on the membrane surface. Our findings provide a robust molecular understanding of mitochondrial membrane perforation by cell-killing Bax protein and illuminate the initial phases of programmed cellular death. Bax initiates apoptosis by perforating mitochondrial membranes via formation of pores and extramembranous Bax-lipid complexes.

sted, utgiver, år, opplag, sider
American Association for the Advancement of Science (AAAS), 2023
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-209321 (URN)10.1126/sciadv.adg7940 (DOI)001009737900018 ()37267355 (PubMedID)2-s2.0-85160903390 (Scopus ID)
Konferanse
2023/06/07
Forskningsfinansiär
Swedish Research Council, 2021-00167Swedish Research Council, 2016-06963The Kempe Foundations, JCK-132
Tilgjengelig fra: 2023-06-08 Laget: 2023-06-08 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Clifton, L. A., Ul Mushtaq, A., Ådén, J., Sparrman, T., Wacklin-Knecht, H. & Gröbner, G. (2023). Insight into Bcl-2 proteins' functioning at mitochondrial membrane level. Biophysical Journal, 122(3S1), 232a-232a, Article ID 1130-Pos.
Åpne denne publikasjonen i ny fane eller vindu >>Insight into Bcl-2 proteins' functioning at mitochondrial membrane level
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2023 (engelsk)Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 122, nr 3S1, s. 232a-232a, artikkel-id 1130-PosArtikkel i tidsskrift, Meeting abstract (Fagfellevurdert) Published
Abstract [en]

Programmed cell death (apoptosis) is essential in life. In its intrinsic apoptotic pathway opposing members of the B-cell lymphoma 2 (Bcl-2) protein family control the permeability of the mitochondrial outer membrane (MOM) and the release of apoptotic factors such as cytochrome c. Any misregulation of this process can cause disorders most prominently cancer, where often upregulation of cell protecting (anti-apoptotic) Bcl-2 members such as the Bcl-2 membrane protein itself plays a notorious role by blocking MOM perforation by - often drug induced - apoptotic proteins such as Bax which would cause cancer cell death normally. Here, we apply neutron reflectometry (NR) on supported lipid bilayers which mimic MOM environment and solid state/liquid state NMR spectroscopy to unravel the molecular basis driving opposing proteins to interact with each other at the MOM; a mechanism which is not really understood yet due to lack of high-resolution structural insight. Based on our central hypothesis that Bcl-2 drives its cell-protecting function at a membrane-embedded location as revealed by NR (1), we focus i) to determine the structure of human Bcl-2 protein in its membrane setting by combining solution and solid-state NMR; ii) use NR to study the kinetics and lipid/protein pore assemblied upon binding of Bax to mitochondrial membranes and its membrane destroying activities there; and iii) unravel the nature of direct interaction between Bcl-2 and Bax to neutralize each other. Knowledge generated here, will be indispensable in understanding the regulative function of the Bcl-2 family at mitochondrial membranes.

sted, utgiver, år, opplag, sider
Elsevier, 2023
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-205180 (URN)10.1016/j.bpj.2022.11.1366 (DOI)36783142 (PubMedID)2-s2.0-85148107754 (Scopus ID)
Tilgjengelig fra: 2023-02-28 Laget: 2023-02-28 Sist oppdatert: 2023-02-28bibliografisk kontrollert
Dulko-Smith, B., Ojeda-May, P., Ådén, J., Wolf-Watz, M. & Nam, K. (2023). Mechanistic basis for a connection between the catalytic step and slow opening dynamics of adenylate kinase. Journal of Chemical Information and Modeling, 63(5), 1556-1569
Åpne denne publikasjonen i ny fane eller vindu >>Mechanistic basis for a connection between the catalytic step and slow opening dynamics of adenylate kinase
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2023 (engelsk)Inngår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 63, nr 5, s. 1556-1569Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Escherichia coli adenylate kinase (AdK) is a small, monomeric enzyme that synchronizes the catalytic step with the enzyme’s conformational dynamics to optimize a phosphoryl transfer reaction and the subsequent release of the product. Guided by experimental measurements of low catalytic activity in seven single-point mutation AdK variants (K13Q, R36A, R88A, R123A, R156K, R167A, and D158A), we utilized classical mechanical simulations to probe mutant dynamics linked to product release, and quantum mechanical and molecular mechanical calculations to compute a free energy barrier for the catalytic event. The goal was to establish a mechanistic connection between the two activities. Our calculations of the free energy barriers in AdK variants were in line with those from experiments, and conformational dynamics consistently demonstrated an enhanced tendency toward enzyme opening. This indicates that the catalytic residues in the wild-type AdK serve a dual role in this enzyme’s function─one to lower the energy barrier for the phosphoryl transfer reaction and another to delay enzyme opening, maintaining it in a catalytically active, closed conformation for long enough to enable the subsequent chemical step. Our study also discovers that while each catalytic residue individually contributes to facilitating the catalysis, R36, R123, R156, R167, and D158 are organized in a tightly coordinated interaction network and collectively modulate AdK’s conformational transitions. Unlike the existing notion of product release being rate-limiting, our results suggest a mechanistic interconnection between the chemical step and the enzyme’s conformational dynamics acting as the bottleneck of the catalytic process. Our results also suggest that the enzyme’s active site has evolved to optimize the chemical reaction step while slowing down the overall opening dynamics of the enzyme.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2023
HSV kategori
Forskningsprogram
biologisk kemi
Identifikatorer
urn:nbn:se:umu:diva-205159 (URN)10.1021/acs.jcim.2c01629 (DOI)000936859400001 ()36802243 (PubMedID)2-s2.0-85148862970 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2021-04513NIH (National Institutes of Health), R01GM132481
Tilgjengelig fra: 2023-02-24 Laget: 2023-02-24 Sist oppdatert: 2023-03-17bibliografisk kontrollert
Ul Mushtaq, A., Ådén, J., Alam, A., Sjöstedt, A. & Gröbner, G. (2022). Backbone chemical shift assignment and dynamics of the N-terminal domain of ClpB from Francisella tularensis type VI secretion system. Biomolecular NMR Assignments, 16, 75-79
Åpne denne publikasjonen i ny fane eller vindu >>Backbone chemical shift assignment and dynamics of the N-terminal domain of ClpB from Francisella tularensis type VI secretion system
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2022 (engelsk)Inngår i: Biomolecular NMR Assignments, ISSN 1874-2718, E-ISSN 1874-270X, Vol. 16, s. 75-79Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The Hsp100 family member ClpB is a protein disaggregase which solubilizes and reactivates stress-induced protein aggregates in cooperation with the DnaK/Hsp70 chaperone system. In the pathogenic bacterium Francisella tularensis, ClpB is involved in type VI secretion system (T6SS) disassembly through depolymerization of the IglA-IglB sheath. This leads to recycling and reassembly of T6SS components and this process is essential for the virulence of the bacterium. Here we report the backbone chemical shift assignments and 15N relaxation-based backbone dynamics of the N-terminal substrate-binding domain of ClpB (1-156).

sted, utgiver, år, opplag, sider
Springer, 2022
Emneord
15N relaxation, ClpB chaperone, Francisella tularensis, NMR resonance assignment, Type VI secretion system
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-191275 (URN)10.1007/s12104-021-10062-3 (DOI)000739320300001 ()34985724 (PubMedID)2-s2.0-85122286521 (Scopus ID)
Forskningsfinansiär
Swedish Research CouncilSwedish Cancer SocietyThe Kempe FoundationsKnut and Alice Wallenberg Foundation
Tilgjengelig fra: 2022-01-13 Laget: 2022-01-13 Sist oppdatert: 2023-03-24bibliografisk kontrollert
Ul Mushtaq, A., Ådén, J., Ali, K. & Gröbner, G. (2022). Domain-specific insight into the recognition of BH3-death motifs by the pro-survival Bcl-2 protein. Biophysical Journal, 121(23), 4517-4525
Åpne denne publikasjonen i ny fane eller vindu >>Domain-specific insight into the recognition of BH3-death motifs by the pro-survival Bcl-2 protein
2022 (engelsk)Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 121, nr 23, s. 4517-4525Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Programmed mammalian cell death (apoptosis) is an essential mechanism in life that tightly regulates embryogenesis and removal of dysfunctional cells. In its intrinsic (mitochondrial) pathway, opposing members of the Bcl-2 (B cell lymphoma 2) protein family meet at the mitochondrial outer membrane (MOM) to control its integrity. Any imbalance can cause disorders, with upregulation of the cell-guarding antiapoptotic Bcl-2 protein itself being common in many, often incurable, cancers. Normally, the Bcl-2 protein itself is embedded in the MOM where it sequesters cell-killing apoptotic proteins such as Bax (Bcl-2-associated X protein) that would otherwise perforate the MOM and subsequently cause cell death. However, the molecular basis of Bcl-2’s ability to recognize those apoptotic proteins via their common BH3 death motifs remains elusive due to the lack of structural insight. By employing nuclear magnetic resonance on fully functional human Bcl-2 protein in membrane-mimicking micelles, we identified glycine residues across all functional domains of the Bcl-2 protein and could monitor their residue-specific individual response upon the presence of a Bax-derived 36aa long BH3 domain. The observed chemical shift perturbations allowed us to determine the response and individual affinity of each glycine residue and provide an overall picture of the individual roles by which Bcl-2’s functional domains engage in recognizing and inhibiting apoptotic proteins via their prominent BH3 motifs. This way, we provide a unique residue- and domain-specific insight into the molecular functioning of Bcl-2 at the membrane level, an insight also opening up for interfering with this cell-protecting mechanism in cancer therapy.

sted, utgiver, år, opplag, sider
Elsevier, 2022
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-201021 (URN)10.1016/j.bpj.2022.10.041 (DOI)000908349700011 ()2-s2.0-85142005196 (Scopus ID)
Forskningsfinansiär
Swedish Research CouncilSwedish Cancer SocietyThe Kempe FoundationsKnut and Alice Wallenberg Foundation
Tilgjengelig fra: 2022-11-15 Laget: 2022-11-15 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Nadeem, A., Berg, A., Pace, H., Alam, A., Toh, E., Ådén, J., . . . Wai, S. N. (2022). Protein-lipid interaction at low pH induces oligomerization of the MakA cytotoxin from Vibrio cholerae. eLIFE, 11, Article ID e73439.
Åpne denne publikasjonen i ny fane eller vindu >>Protein-lipid interaction at low pH induces oligomerization of the MakA cytotoxin from Vibrio cholerae
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2022 (engelsk)Inngår i: eLIFE, E-ISSN 2050-084X, Vol. 11, artikkel-id e73439Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The α-pore-forming toxins (α-PFTs) from pathogenic bacteria damage host cell membranes by pore formation. We demonstrate a remarkable, hitherto unknown mechanism by an α-PFT protein from Vibrio cholerae. As part of the MakA/B/E tripartite toxin, MakA is involved in membrane pore formation similar to other α-PFTs. In contrast, MakA in isolation induces tube-like structures in acidic endosomal compartments of epithelial cells in vitro. The present study unravels the dynamics of tubular growth, which occurs in a pH-, lipid-, and concentration-dependent manner. Within acidified organelle lumens or when incubated with cells in acidic media, MakA forms oligomers and remodels membranes into high-curvature tubes leading to loss of membrane integrity. A 3.7 Å cryo-electron microscopy structure of MakA filaments reveals a unique protein-lipid superstructure. MakA forms a pinecone-like spiral with a central cavity and a thin annular lipid bilayer embedded between the MakA transmembrane helices in its active α-PFT conformation. Our study provides insights into a novel tubulation mechanism of an α-PFT protein and a new mode of action by a secreted bacterial toxin.

sted, utgiver, år, opplag, sider
eLife Sciences Publications, Ltd, 2022
Emneord
Vibrio cholerae, MakA, lipid
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-192300 (URN)10.7554/eLife.73439 (DOI)2-s2.0-85124321786 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2018–02914Swedish Research Council, 2016–05009Swedish Research Council, 2019–01720Swedish Research Council, 2016–06963Swedish Research Council, 2019–02011Swedish Cancer Society, 2017–419Swedish Cancer Society, 2020–711The Kempe Foundations, JCK-1728The Kempe Foundations, SMK-1756.2The Kempe Foundations, SMK-1553The Kempe Foundations, JCK-1724The Kempe Foundations, SMK-1961Knut and Alice Wallenberg FoundationFamiljen Erling-Perssons Stiftelse
Tilgjengelig fra: 2022-02-08 Laget: 2022-02-08 Sist oppdatert: 2024-01-12bibliografisk kontrollert
Ul Mushtaq, A., Ådén, J., Sparrman, T., Hedenström, M. & Gröbner, G. (2021). Insight into Functional Membrane Proteins by Solution NMR: The Human Bcl-2 Protein - A Promising Cancer Drug Target. Molecules, 26(5), Article ID 1467.
Åpne denne publikasjonen i ny fane eller vindu >>Insight into Functional Membrane Proteins by Solution NMR: The Human Bcl-2 Protein - A Promising Cancer Drug Target
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2021 (engelsk)Inngår i: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 26, nr 5, artikkel-id 1467Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Evasion from programmed cell death (apoptosis) is the main hallmark of cancer and a major cause of resistance to therapy. Many tumors simply ensure survival by over-expressing the cell-protecting (anti-apoptotic) Bcl-2 membrane protein involved in apoptotic regulation. However, the molecular mechanism by which Bcl-2 protein in its mitochondrial outer membrane location protects cells remains elusive due to the absence of structural insight; and current strategies to therapeutically interfere with these Bcl-2 sensitive cancers are limited. Here, we present an NMR-based approach to enable structural insight into Bcl-2 function; an approach also ideal as a fragment-based drug discovery platform for further identification and development of promising molecular Bcl-2 inhibitors. By using solution NMR spectroscopy on fully functional intact human Bcl-2 protein in a membrane-mimicking micellar environment, and constructs with specific functions remaining, we present a strategy for structure determination and specific drug screening of functional subunits of the Bcl-2 protein as targets. Using 19F NMR and a specific fragment library (Bionet) with fluorinated compounds we can successfully identify various binders and validate our strategy in the hunt for novel Bcl-2 selective cancer drug strategies to treat currently incurable Bcl-2 sensitive tumors.

sted, utgiver, år, opplag, sider
MDPI, 2021
Emneord
Bcl-2 membrane protein, NMR, drug screening
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-181526 (URN)10.3390/molecules26051467 (DOI)000628449100001 ()2-s2.0-85103920124 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2016-06963Swedish Cancer Society, CAN 2015/482The Kempe FoundationsKnut and Alice Wallenberg Foundation
Tilgjengelig fra: 2021-03-17 Laget: 2021-03-17 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Bharate, J. B., Ådén, J., Gharibyan, A., Adolfsson, D. E., Jayaweera, S. W., Singh, P., . . . Almqvist, F. (2021). K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones. Organic and biomolecular chemistry, 19(44), 9758-9772
Åpne denne publikasjonen i ny fane eller vindu >>K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones
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2021 (engelsk)Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 19, nr 44, s. 9758-9772Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.

sted, utgiver, år, opplag, sider
The Royal Society of Chemistry, 2021
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-189516 (URN)10.1039/D1OB01580J (DOI)000714122800001 ()34730163 (PubMedID)2-s2.0-85120001225 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2017-02339; 2017-00695; 2018-04589Knut and Alice Wallenberg Foundation, 2013.0031Göran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Foundation for Strategic Research, SB12-0070NIH (National Institutes of Health), (R01AI134847-01A1
Tilgjengelig fra: 2021-11-15 Laget: 2021-11-15 Sist oppdatert: 2023-08-09bibliografisk kontrollert
Ul Mushtaq, A., Ådén, J., Clifton, L. A., Wacklin-Knecht, H., Campana, M., Dingeldein, A. P. G., . . . Gröbner, G. (2021). Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation. Communications Biology, 4(1), Article ID 507.
Åpne denne publikasjonen i ny fane eller vindu >>Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation
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2021 (engelsk)Inngår i: Communications Biology, E-ISSN 2399-3642, Vol. 4, nr 1, artikkel-id 507Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane location of Bcl-2 and its conformational state seems to be important for its cell-protecting activity, often infamously upregulated in cancers. Most likely, this situation enables the Bcl-2 protein to sequester pro-apoptotic Bcl-2 proteins at the membrane level while sensing cytosolic regulative signals via its FLD region.

sted, utgiver, år, opplag, sider
Springer Nature, 2021
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-182710 (URN)10.1038/s42003-021-02032-1 (DOI)000647062000003 ()2-s2.0-85105112344 (Scopus ID)
Forskningsfinansiär
Swedish Research CouncilSwedish Cancer SocietyThe Kempe FoundationsKnut and Alice Wallenberg Foundation
Tilgjengelig fra: 2021-05-04 Laget: 2021-05-04 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Näsström, T., Dahlberg, T., Malyshev, D., Ådén, J., Andersson, P. O., Andersson, M. & Karlsson, B. C. G. (2021). Synthetic NAC 71-82 Peptides Designed to Produce Fibrils with Different Protofilament Interface Contacts. International Journal of Molecular Sciences, 22(17), Article ID 9334.
Åpne denne publikasjonen i ny fane eller vindu >>Synthetic NAC 71-82 Peptides Designed to Produce Fibrils with Different Protofilament Interface Contacts
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2021 (engelsk)Inngår i: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, nr 17, artikkel-id 9334Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Alpha-synucleinopathies are featured by fibrillar inclusions in brain cells. Although α-synuclein fibrils display structural diversity, the origin of this diversity is not fully understood. We used molecular dynamics simulations to design synthetic peptides, based on the NAC 71-82 amino acid fragment of α-synuclein, that govern protofilament contacts and generation of twisted fibrillar polymorphs. Four peptides with structures based on either single or double fragments and capped or non-capped ends were selected for further analysis. We determined the fibrillar yield and the structures from these peptides found in the solution after fibrillisation using protein concentration determination assay and circular dichroism spectroscopy. In addition, we characterised secondary structures formed by individual fibrillar complexes using laser-tweezers Raman spectroscopy. Results suggest less mature fibrils, based on the lower relative β-sheet content for double- than single-fragment peptide fibrils. We confirmed this structural difference by TEM analysis which revealed, in addition to short protofibrils, more elongated, twisted and rod-like fibril structures in non-capped and capped double-fragment peptide systems, respectively. Finally, time-correlated single-photon counting demonstrated a difference in the Thioflavin T fluorescence lifetime profiles upon fibril binding. It could be proposed that this difference originated from morphological differences in the fibril samples. Altogether, these results highlight the potential of using peptide models for the generation of fibrils that share morphological features relevant for disease, e.g., twisted and rod-like polymorphs.

sted, utgiver, år, opplag, sider
MDPI, 2021
Emneord
α-synuclein, NAC 71-82 peptides, fibril polymorphs
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-186977 (URN)10.3390/ijms22179334 (DOI)000694357900001 ()2-s2.0-85113788315 (Scopus ID)
Tilgjengelig fra: 2021-08-29 Laget: 2021-08-29 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-4480-1219