Lipid domain boundary triggers membrane damage and protein folding of human islet amyloid polypeptide in the early pathogenesis of amyloid diseases

Lewis, Amber; Pham, Thuong; Nguyên, Ngoc Thanh; Graf, Angela; Cheng, Kwan Hon

doi:10.1016/j.bpc.2023.106993

Cited by 6 publications

(25 citation statements)

References 51 publications

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“…These transversely asymmetric distributions of nanodomains, therefore, provide different potential membrane targets for the attachment of misfolded hIAPP aggregates on cell membranes. As demonstrated in a recent study [ 16 ], in the absence of PS-clusters or GM1-clusters, disordered hIAPP oligomers of all sizes exclusively bind to the Lod domain of the CO-raft. However, in the presence of PS-clusters or GM1-clusters, these hIAPP oligomers exclusively bind to PS-clusters or GM1-clusters rather than to Lod domains.…”

Section: Discussionmentioning

confidence: 73%

“…Regarding the PS-raft or GM-raft, PS-clusters within the Lod domain or GM1-clusters within the Lo domain on one lipid leaflet are observed, respectively. Details on the construction, energy minimization, position-restraining equilibration, and unconstrained CG MD simulation of protein membranes in the NPT ensemble based on Martini CG forcefields [ 41 ] and ran on the GROMACS-4.6.7 MD simulation program [ 42 ] can be found elsewhere [ 16 , 17 , 18 , 30 ]. All simulations were carried out under the physiological conditions of 0.1 M NaCl, 310 K, and 1-atmosphere pressure as described above.…”

Section: Methodsmentioning

confidence: 99%

“…All CG simulations were performed under the physiological conditions of 0.1 M NaCl, 310 K, and 1-atmosphere pressure. The procedures and conditions of MD simulations of CG [hIAPP] n in solution identical to those of raft membranes in solution are described above [ 16 , 17 , 18 ]. All construction tools were based on the GROMACS-MD simulation program package and are described in detail in our previous studies [ 16 , 17 , 18 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…To explore the molecular mechanisms of hIAPP-induced membrane damage, we have designed a 37-residue-long disordered hIAPP monomer [ 15 , 16 ]. Disordered monomers, and self-aggregated dimers and tetramers, or hIAPP oligomers, in solution were subsequently constructed using a coarse-grained (CG) model [ 16 ]. For the lipid membrane, we have designed several multi-component phase-separated lipid bilayers, or raft membranes, containing dynamic lipid nanodomains as our lipid membrane model to investigate protein-induced membrane damage by disordered hIAPP oligomers on lipid nanodomains of different nanostructures [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations

et al. 2023

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The aggregation of human Islet Amyloid Polypeptide (hIAPP) on cell membranes is linked to amyloid diseases. However, the physio-chemical mechanisms of how these hIAPP aggregates trigger membrane damage are unclear. Using coarse-grained and all-atom molecular dynamics simulations, we investigated the role of lipid nanodomains in the presence or absence of anionic lipids, phosphatidylserine (PS), and a ganglioside (GM1), in the membrane disruption and protein folding behaviors of hIAPP aggregates on phase-separated raft membranes. Our raft membranes contain liquid-ordered (Lo), liquid-disordered (Ld), mixed Lo/Ld (Lod), PS-cluster, and GM1-cluster nanosized domains. We observed that hIAPP aggregates bound to the Lod domain in the absence of anionic lipids, but also to the GM1-cluster- and PS-cluster-containing domains, with stronger affinity in the presence of anionic lipids. We discovered that L16 and I26 are the lipid anchoring residues of hIAPP binding to the Lod and PS-cluster domains. Finally, significant lipid acyl chain order disruption in the annular lipid shells surrounding the membrane-bound hIAPP aggregates and protein folding, particularly beta-sheet formation, in larger protein aggregates were evident. We propose that the interactions of hIAPP and both non-anionic and anionic lipid nanodomains represent key molecular events of membrane damage associated with the pathogenesis of amyloid diseases.

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Section: Discussionmentioning

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations

et al. 2023

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Crosstalk Between NK Cell Receptors and Tumor Membrane Hsp70‐Derived Peptide: A Combined Computational and Experimental Study

Yazdi,

Hasanzadeh Kafshgari,

Khademi Moghadam

et al. 2024

Advanced Science

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Natural killer (NK) cells are central components of the innate immunity system against cancers. Since tumor cells have evolved a series of mechanisms to escape from NK cells, developing methods for increasing the NK cell antitumor activity is of utmost importance. It is previously shown that an ex vivo stimulation of patient‐derived NK cells with interleukin (IL)‐2 and Hsp70‐derived peptide TKD (TKDNNLLGRFELSG, aa450‐461) results in a significant upregulation of activating receptors including CD94 and CD69 which triggers exhausted NK cells to target and kill malignant solid tumors expressing membrane Hsp70 (mHsp70). Considering that TKD binding to an activating receptor is the initial step in the cytolytic signaling cascade of NK cells, herein this interaction is studied by molecular docking and molecular dynamics simulation computational modeling. The in silico results showed a crucial role of the heterodimeric receptor CD94/NKG2A and CD94/NKG2C in the TKD interaction with NK cells. Antibody blocking and CRISPR/Cas9–mediated knockout studies verified the key function of CD94 in the TKD stimulation and activation of NK cells which is characterized by an increased cytotoxic capacity against mHsp70 positive tumor cells via enhanced production and release of lytic granules and pro‐inflammatory cytokines.

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Effect of phospholipid liposomes on prion fragment (106–128) amyloid formation

Regmi,

Shen,

Stanic

et al. 2023

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Lipid domain boundary triggers membrane damage and protein folding of human islet amyloid polypeptide in the early pathogenesis of amyloid diseases

Cited by 6 publications

References 51 publications

Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations

Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations

Crosstalk Between NK Cell Receptors and Tumor Membrane Hsp70‐Derived Peptide: A Combined Computational and Experimental Study

Effect of phospholipid liposomes on prion fragment (106–128) amyloid formation

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