Emily Lewkowicz

Boston University

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i-10 index

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Olga Gursky

Boston University

Michael J. Rynkiewicz

Boston University

Mari N. Nakamura

Middlebury College

Shobini Jayaraman

Boston University

Dustin D. Luu

Arizona State University

Shankar Raj Devkota

Australian Regenerative Medicine Institute

Jarrod Shilts

National Institute of Immunology

Christopher Councilor

Universidad del Noreste

Rafael Alvarez Gonzalez

Weizmann Institute of Science

Swati Balakrishnan

Vanderbilt University

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Vanderbilt University

Johns Hopkins University

University of Massachusetts Amherst

Massachusetts Institute of Technology

University of California, Berkeley

Boston University

Universidad del Noreste

University of Pennsylvania

University of North Carolina at Chapel Hill

Pennsylvania State University

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Molecular modeling of apoE interactions with amyloid-beta fibrils from human brain suggests a structural basis for apolipoprotein co-deposition with amyloids PC1 (#28)

Olga Gursky Emily Lewkowicz J. Michael Wyss

Apolipoprotein E

Amyloid (mycology)

BETA (programming language)

Deposition

Basis (linear algebra)

10.26226/m.65f9bf89e6f73964e1d4e865

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Molecular modeling of apoE in complexes with Alzheimer’s amyloid-β fibrils from human brain suggests a structural basis for apolipoprotein co-deposition with amyloids

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Emily Lewkowicz Mari N. Nakamura Michael J. Rynkiewicz Olga Gursky

Apolipoproteins co-deposit with amyloids, yet apolipoprotein-amyloid interactions are enigmatic. To understand how apoE interacts with Alzheimer's amyloid-β (Aβ) peptide in fibrillary deposits, the NMR structure of full-length human apoE was docked to four structures of patient-derived Aβ1-40 and Aβ1-42 fibrils determined previously using cryo-electron microscopy or solid-state NMR. Similar docking was done using the NMR structure of human apoC-III. In all complexes, conformational changes in apolipoproteins were required to expose large hydrophobic faces of their amphipathic α-helices for sub-stoichiometric binding to hydrophobic surfaces on sides or ends of fibrils. Basic residues flanking the hydrophobic helical faces in apolipoproteins interacted favorably with acidic residue ladders in some amyloid polymorphs. Molecular dynamics simulations of selected apoE-fibril complexes confirmed their stability. Amyloid binding via cryptic sites, which became available upon opening of flexibly linked apolipoprotein α-helices, resembled apolipoprotein-lipid binding. This mechanism probably extends to other apolipoprotein-amyloid interactions. Apolipoprotein binding alongside fibrils could interfere with fibril fragmentation and secondary nucleation, while binding at the fibril ends could halt amyloid elongation and dissolution in a polymorph-specific manner. The proposed mechanism is supported by extensive prior experimental evidence and helps reconcile disparate reports on apoE's role in Aβ aggregation. Furthermore, apoE domain opening and direct interaction of Arg/Cys158 with amyloid potentially contributes to isoform-specific effects in Alzheimer's disease. In summary, current modeling supported by prior experimental studies suggests similar mechanisms for apolipoprotein-amyloid and apolipoprotein-lipid interactions; explains why apolipoproteins co-deposit with amyloids; and helps reconcile conflicting reports on the chaperone-like apoE action in Aβ aggregation.

Apolipoprotein E

Amyloid (mycology)

Fibrillogenesis

10.1101/2023.08.04.551703

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Citations (1)

Dynamic protein structures in normal function and pathologic misfolding in systemic amyloidosis

Biophysical Chemistry (2021)

Emily Lewkowicz Olga Gursky

Amyloid (mycology)

Amyloid disease

10.1016/j.bpc.2021.106699

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Citations (12)

Issue information

Protein Science (2022)

San Francisco Walter Chazin Julie D. Forman‐Kay Steven M. Damo Bruno E. Correia

The Protein Society is a not-for-profit scholarly society with a mission to advance state-of-the-art science through international forums that promote communication, cooperation, and collaboration among scientists involved in the study of proteins.For 36 years, The Protein Society has served as the intellectual home of investigators across all disciplines -and from around the world -involved in the study of protein structure, function, and design.The Society provides forums for scientific collaboration and communication and supports professional growth of young investigators through workshops, networking opportunities, and by encouraging junior researchers to participate fully in the Annual Symposium.In addition to our Symposium, the Society's prestigious journal, Protein Science, serves as an ideal platform to further the science of proteins in the broadest sense possible.

10.1002/pro.4546

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Elucidating the Mechanism of Recognition and Binding of Heparin to Amyloid Fibrils of Serum Amyloid A

Biochemistry (2024)

Conor B. Abraham Emily Lewkowicz Olga Gursky John E. Straub

Amyloid diseases feature pathologic deposition of normally soluble proteins and peptides as insoluble fibrils in vital organs. Amyloid fibrils co-deposit with various nonfibrillar components including heparan sulfate (HS), a glycosaminoglycan that promotes amyloid formation in vitro for many unrelated proteins. HS-amyloid interactions have been proposed as a therapeutic target for inflammation-linked amyloidosis wherein N-terminal fragments of serum amyloid A (SAA) protein deposit in the kidney and liver. The structural basis for these interactions is unclear. Here, we exploit the high-resolution cryoelectron microscopy (cryo-EM) structures of ex vivo murine and human SAA fibrils in a computational study employing molecular docking, Brownian dynamics simulations, and molecular dynamics simulations to elucidate how heparin, a highly sulfated HS mimetic, recognizes and binds to amyloid protein fibrils. Our results demonstrate that negatively charged heparin chains bind to linear arrays of uncompensated positively charged basic residues along the spines of amyloid fibrils facilitated by electrostatic steering. The predicted heparin binding sites match the location of unidentified densities observed in cryo-EM maps of SAA amyloids, suggesting that these extra densities represent bound HS. Since HS is constitutively found in various amyloid deposits, our results suggest a common mechanism for HS-amyloid recognition and binding.

Amyloid (mycology)

10.1021/acs.biochem.4c00529

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Citations (1)

Protein Amyloid Cofactors: Charged Side-Chain Arrays Meet Their Match?

Trends in Biochemical Sciences (2021)

Emily Lewkowicz Shobini Jayaraman Olga Gursky

Amyloid (mycology)

Side chain

10.1016/j.tibs.2021.05.003

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Citations (25)

Molecular basis for non-invasive diagnostics of cardiac amyloids using bone tracers

Biomaterials Science (2024)

Emily Lewkowicz Shobini Jayaraman Olga Gursky

Amyloid diseases including Alzheimer's, Parkinson's and over 30 others are incurable life-threatening disorders caused by abnormal protein deposition as fibrils in various organs. Cardiac amyloidosis is particularly challenging to diagnose and treat. Identification of the fibril-forming protein, which in the heart is usually amyloid transthyretin (ATTR) or amyloid immunoglobulin light chain (AL), is paramount to treatment. A transformative non-invasive diagnostic modality is imaging using technetium-labeled pyrophosphate or diphosphonate bone tracers,

10.1039/d4bm00816b

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Citations (3)

Molecular modeling of apoE in complexes with Alzheimer’s amyloid-β fibrils from human brain suggests a structural basis for apolipoprotein co-deposition with amyloids

Cellular and Molecular Life Sciences (2023)

Emily Lewkowicz Mari N. Nakamura Michael J. Rynkiewicz Olga Gursky

Apolipoprotein E

Amyloid (mycology)

10.1007/s00018-023-05026-w

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Citations (6)