Direct Observation of Seeded Conformational Conversion of HIAPP Reveals the Mechanisms for Morphological Dependence and Asymmetry of Fibril Growth

Overview

Journal J Chem Inf Model

Publisher American Chemical Society

Specialties Chemistry
Medical Informatics

Date 2023 Aug 31

PMID 37651616

Authors

Gangtong Huang

Huayuan Tang

Yuying Liu

Chi Zhang

Pu Chun Ke

Yunxiang Sun

Feng Ding

Affiliations

Soon will be listed here.

Abstract

Rapid growth of amyloid fibrils a seeded conformational conversion of monomers is a critical step of fibrillization and important for disease transmission and progression. Amyloid fibrils often display diverse morphologies with distinct populations, and yet the molecular mechanisms of fibril elongation and their corresponding morphological dependence remain poorly understood. Here, we computationally investigated the single-molecular growth of two experimentally resolved human islet amyloid polypeptide fibrils of different morphologies. In both cases, the incorporation of monomers into preformed fibrils was observed. The conformational conversion dynamics was characterized by a small number of fibril growth intermediates. Fibril morphology affected monomer binding at fibril elongation and lateral surfaces as well as the seeded conformational conversion dynamics at the fibril ends, resulting in different fibril elongation rates and populations. We also observed an asymmetric fibril growth as in our prior experiments, attributing to differences of two fibril ends in terms of their local surface curvatures and exposed hydrogen-bond donors and acceptors. Together, our mechanistic findings afforded a theoretical basis for delineating different amyloid strains-entailed divergent disease progression.

Citing Articles

Impact of frequent ARID1A mutations on protein stability provides insights into cancer pathogenesis.

Goutam R, Huang G, Medina E, Ding F, Edenfield W, Sanabria H Sci Rep. 2025; 15(1):3072.

PMID: 39856215 PMC: 11760938. DOI: 10.1038/s41598-025-87103-7.

Impact of Frequent ARID1A Mutations on Protein Stability: Insights into Cancer Pathogenesis.

Goutam R, Huang G, Medina E, Ding F, Edenfield W, Sanabria H Res Sq. 2025; .

PMID: 39764114 PMC: 11702796. DOI: 10.21203/rs.3.rs-5225582/v1.

Deciphering the Morphological Difference of Amyloid-β Fibrils in Familial and Sporadic Alzheimer's Diseases.

Huang G, Song Z, Xu Y, Sun Y, Ding F J Chem Inf Model. 2024; 64(20):8024-8033.

PMID: 39382320 PMC: 11590496. DOI: 10.1021/acs.jcim.4c01471.

Islet amyloid polypeptide fibril catalyzes amyloid-β aggregation by promoting fibril nucleation rather than direct axial growth.

Song Z, Tang H, Gatch A, Sun Y, Ding F Int J Biol Macromol. 2024; 279(Pt 1):135137.

PMID: 39208885 PMC: 11469950. DOI: 10.1016/j.ijbiomac.2024.135137.

Computational Investigation of Coaggregation and Cross-Seeding between Aβ and hIAPP Underpinning the Cross-Talk in Alzheimer's Disease and Type 2 Diabetes.

Fan X, Zhang X, Yan J, Xu H, Zhao W, Ding F J Chem Inf Model. 2024; 64(13):5303-5316.

PMID: 38921060 PMC: 11339732. DOI: 10.1021/acs.jcim.4c00859.

References

Cohen S, Linse S, Luheshi L, Hellstrand E, White D, Rajah L . Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism. Proc Natl Acad Sci U S A. 2013; 110(24):9758-63. PMC: 3683769. DOI: 10.1073/pnas.1218402110. View

Ke P, Sani M, Ding F, Kakinen A, Javed I, Separovic F . Implications of peptide assemblies in amyloid diseases. Chem Soc Rev. 2017; 46(21):6492-6531. PMC: 5902192. DOI: 10.1039/c7cs00372b. View

Knowles T, Shu W, Devlin G, Meehan S, Auer S, Dobson C . Kinetics and thermodynamics of amyloid formation from direct measurements of fluctuations in fibril mass. Proc Natl Acad Sci U S A. 2007; 104(24):10016-21. PMC: 1891240. DOI: 10.1073/pnas.0610659104. View

Gremer L, Scholzel D, Schenk C, Reinartz E, Labahn J, Ravelli R . Fibril structure of amyloid-β(1-42) by cryo-electron microscopy. Science. 2017; 358(6359):116-119. PMC: 6080689. DOI: 10.1126/science.aao2825. View

Wetzel R . Kinetics and thermodynamics of amyloid fibril assembly. Acc Chem Res. 2006; 39(9):671-9. DOI: 10.1021/ar050069h. View

Ghosh U, Thurber K, Yau W, Tycko R . Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue. Proc Natl Acad Sci U S A. 2021; 118(4). PMC: 7848700. DOI: 10.1073/pnas.2023089118. View

Yanez Orozco I, Mindlin F, Ma J, Wang B, Levesque B, Spencer M . Identifying weak interdomain interactions that stabilize the supertertiary structure of the N-terminal tandem PDZ domains of PSD-95. Nat Commun. 2018; 9(1):3724. PMC: 6137104. DOI: 10.1038/s41467-018-06133-0. View

Gaspar R, Meisl G, Buell A, Young L, Kaminski C, Knowles T . Secondary nucleation of monomers on fibril surface dominates α-synuclein aggregation and provides autocatalytic amyloid amplification. Q Rev Biophys. 2017; 50:e6. DOI: 10.1017/S0033583516000172. View

Ke P, Pilkington E, Sun Y, Javed I, Kakinen A, Peng G . Mitigation of Amyloidosis with Nanomaterials. Adv Mater. 2019; 32(18):e1901690. PMC: 6904546. DOI: 10.1002/adma.201901690. View

10.

Cendrowska U, Silva P, Ait-Bouziad N, Muller M, Pelin Guven Z, Vieweg S . Unraveling the complexity of amyloid polymorphism using gold nanoparticles and cryo-EM. Proc Natl Acad Sci U S A. 2020; 117(12):6866-6874. PMC: 7104366. DOI: 10.1073/pnas.1916176117. View

11.

Madine J, Jack E, Stockley P, Radford S, Serpell L, Middleton D . Structural insights into the polymorphism of amyloid-like fibrils formed by region 20-29 of amylin revealed by solid-state NMR and X-ray fiber diffraction. J Am Chem Soc. 2008; 130(45):14990-5001. DOI: 10.1021/ja802483d. View

12.

Meisl G, Yang X, Hellstrand E, Frohm B, Kirkegaard J, Cohen S . Differences in nucleation behavior underlie the contrasting aggregation kinetics of the Aβ40 and Aβ42 peptides. Proc Natl Acad Sci U S A. 2014; 111(26):9384-9. PMC: 4084462. DOI: 10.1073/pnas.1401564111. View

13.

Colvin M, Silvers R, Ni Q, Can T, Sergeyev I, Rosay M . Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils. J Am Chem Soc. 2016; 138(30):9663-74. PMC: 5389415. DOI: 10.1021/jacs.6b05129. View

14.

Faridi A, Sun Y, Mortimer M, Aranha R, Nandakumar A, Li Y . Graphene quantum dots rescue protein dysregulation of pancreatic β-cells exposed to human islet amyloid polypeptide. Nano Res. 2019; 12(11):2827-2834. PMC: 6834229. DOI: 10.1007/s12274-019-2520-7. View

15.

Sun Y, Ge X, Xing Y, Wang B, Ding F . β-barrel Oligomers as Common Intermediates of Peptides Self-Assembling into Cross-β Aggregates. Sci Rep. 2018; 8(1):10353. PMC: 6037789. DOI: 10.1038/s41598-018-28649-7. View

16.

Gallardo R, Iadanza M, Xu Y, Heath G, Foster R, Radford S . Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly. Nat Struct Mol Biol. 2020; 27(11):1048-1056. DOI: 10.1038/s41594-020-0496-3. View

17.

Heldt C, Zhang S, Belfort G . Asymmetric amyloid fibril elongation: a new perspective on a symmetric world. Proteins. 2010; 79(1):92-8. DOI: 10.1002/prot.22861. View

18.

Gath J, Bousset L, Habenstein B, Melki R, Bockmann A, Meier B . Unlike twins: an NMR comparison of two α-synuclein polymorphs featuring different toxicity. PLoS One. 2014; 9(3):e90659. PMC: 3944079. DOI: 10.1371/journal.pone.0090659. View

19.

OBrien E, Okamoto Y, Straub J, Brooks B, Thirumalai D . Thermodynamic perspective on the dock-lock growth mechanism of amyloid fibrils. J Phys Chem B. 2009; 113(43):14421-30. PMC: 4204656. DOI: 10.1021/jp9050098. View

20.

Beun L, Albertazzi L, van der Zwaag D, de Vries R, Stuart M . Unidirectional Living Growth of Self-Assembled Protein Nanofibrils Revealed by Super-resolution Microscopy. ACS Nano. 2016; 10(5):4973-80. DOI: 10.1021/acsnano.6b01017. View