Exploring the structure and formation mechanism of amyloid fibrils

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Transcript of Exploring the structure and formation mechanism of amyloid fibrils

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    CRITICAL REVIEW

    Cite this: DOI: 10.1039/c5an00342c

    Received 19th February 2015,Accepted 11th May 2015

    DOI: 10.1039/c5an00342c

    www.rsc.org/analyst

    Exploring the structure and formation mechanismof amyloid fibrils by Raman spectroscopy: a review

    Dmitry Kurouski,*a Richard P. Van Duynea and Igor K. Lednevb

    Amyloid fibrils are -sheet rich protein aggregates that are strongly associated with various neurodegen-erative diseases. Raman spectroscopy has been broadly utilized to investigate protein aggregation and

    amyloid fibril formation and has been shown to be capable of revealing changes in secondary and tertiary

    structures at all stages of fibrillation. When coupled with atomic force (AFM) and scanning electron (SEM)

    microscopies, Raman spectroscopy becomes a powerful spectroscopic approach that can investigate the

    structural organization of amyloid fibril polymorphs. In this review, we discuss the applications of Raman

    spectroscopy, a unique, label-free and non-destructive technique for the structural characterization of

    amyloidogenic proteins, prefibrilar oligomers, and mature fibrils.

    1. Introduction

    The rapid aggregation of misfolded proteins is commonlyassociated with various neurodegenerative diseases, such asAlzheimers disease, Parkinsons disease, systematic amyloido-

    sis and type II diabetes.1,2 The post mortem microscopic exam-ination of organs and tissues of patients diagnosed with thesesevere maladies reveals amyloid plaques that contain long,unbranched, rod-like protein aggregates, known as amyloidfibrils.35 Amyloid plaques give a positive iodine stain, whichis typical for cellulose-containing substances. This observationmade Rudolf Virchow conclude that amyloid plaques containstarch. In 1854, he proposed the term amyloid, which meansstarch-containing.6 Despite the later demonstration by Frie-dreich and Kekule that proteins, rather than polysaccharides,

    Dmitry Kurouski

    Dmitry Kurouski earned his M.S.in Biochemistry from BelarusianState University, Belarus and Ph.D.(Distinguished Dissertation) inAnalytical Chemistry from SUNYAlbany, NY, USA. His doctoralthesis was focused on studies ofprotein aggregation and amyloidfibril formation using deep UVresonance (DUVRR), surface(SERS) and tip (TERS) enhancedRaman spectroscopies. In 2012he joined the laboratory ofProfessor Richard P. Van Duyne

    at Northwestern University, where he demonstrated that TERS canbe used to identify the composition of dyes and inks directly onthe artwork. In 2014, he was awarded with the Best JuniorResearcher Award at the 24th International Conference on RamanSpectroscopy (ICORS).

    Richard P. Van Duyne

    Richard P. Van Duyne is CharlesE. and Emma H. MorrisonProfessor of Chemistry andof Biomedical Engineering atNorthwestern University. Hereceived a BS (1967) fromRensselaer Polytechnic Instituteand PhD (1971) from the Univer-sity of North Carolina, ChapelHill, both in Chemistry. He is amember of the NationalAcademy of Sciences and theAmerican Academy of Arts andSciences. He is known for the dis-

    covery of surface-enhanced Raman spectroscopy (SERS), the inven-tion of nanosphere lithography (NSL), and the development ofultrasensitive nanosensors based on localized surface plasmonresonance (LSPR) spectroscopy.

    aDepartment of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston,

    Illinois, USA. E-mail: dkurouski@northwestern.edubDepartment of Chemistry, University at Albany, State University of New York,

    1400 Washington Ave., Albany, USA

    This journal is The Royal Society of Chemistry 2015 Analyst

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  • are the main component of amyloid plaques, the termamyloid continued to be utilized to describe -sheet richprotein aggregates.7

    There are several hypotheses on how amyloid fibrils form.One hypothesis suggests that rapid protein aggregation isinitiated inside multivesicular bodies.8 As a result, prefibrilaroligomers are formed. Uncontrollable growth of these aggre-gates leads to the destruction of the cell integrity and a releaseof fibril species into the extracellular space. The fibril speciesthen propagate into amyloid fibrils. According to the secondhypothesis, fibril formation is a defense mechanism that isaimed to isolate highly toxic misfolded proteins and theiroligomers from the cell media, by packing them into themuch less toxic fibrillar form.9,10 In vitro studies have revealedthat more than 25 proteins can aggregate forming fibrils.1,5,11

    Protein aggregation typically exhibits a lag phase, followed by arapid elongation phase, and then an asymptotic phase.1,12,13

    During the lag phase, soluble prefibrilar oligomers aggregatein multiple assembly states forming a nucleus. The nuclei tem-plate protein aggregation, causing the formation of fibrils.1315

    Raman spectroscopy has been broadly used to investigatechanges in secondary structure at all stages of protein aggrega-tion and amyloid fibril formation.1618 In particular, normalRaman (NR) spectroscopy is commonly used to elucidateconformations of disulfides in both proteins and amyloidfibrils.19,20 Coupling of hydrogendeuterium exchange (H/Dexchange) with deep UV Raman (DUVRR) spectroscopy allowsone to elucidate fibril core structural organization and deter-mine the psi () dihedral angle of the protein backbone.18,2123

    In addition, DUVRR provides valuable information about thelocal environment near aromatic amino acids, such as phenyl-alanine and tyrosine. This can be utilized to monitor thechanges in protein secondary structure that occur uponprotein aggregation.14,24 Recently, the combination of Ramanspectroscopy with atomic force microscopy (AFM) or scanning

    electron microscopy (SEM) has become a powerful analyticalapproach for investigating the structural organization of fibrilpolymorphs.2527 Fibril polymorphism is a unique phenom-enon that occurs when fibrils with different morphologies andsecondary structures are grown from the same protein thataggregates at slightly different temperatures, pH values, orother experimental conditions.27

    Surface-enhanced Raman spectroscopy (SERS) has alsobeen utilized to probe the surface organization of macroscopicobjects, such as viruses and amyloid fibrils. SERS is an ultra-sensitive technique that was discovered in 1977 by Jeanmaireand Van Duyne.28 When a molecule is located within 12 nmof a noble metal nanostructure, there is drastic amplificationof the Raman signal. It was also demonstrated that the electro-magnetic enhancement exponentially decays as the distancefrom the metal nanostructures increases.29,30 This advantagemade surface-enhanced Raman spectroscopy a widelyused analytical approach for the detection and identificationof various analytes, ranging from warfare agents tobiomolecules.3134 Tip-enhanced Raman spectroscopy (TERS)combines the sensitivity of SERS and the precise spatialcontrol of scanning probe microscopy (SPM) via a nanometerscale noble metal tip.3537 AFM based TERS (AFM-TERS) hasbeen utilized to obtain information about the structural organi-zation of the insulin fibril surface at the nanoscale.38,39

    Using TERS, information about the amino acid compositionof amyloid fibrils and protein secondary structure on theirsurfaces can be obtained. Furthermore, TERS and SERS spectraacquired from large protein molecules and their aggregates areusually quite different from NR spectra of these species.35,40

    2. Physical principles of the Ramaneffect

    Upon the illumination of a molecule with electromagneticradiation, an exchange of a quantum vibrational energybetween the two occurs, resulting in a vibrational frequencydifference between the incident and scattered light. Thisinelastic scattering phenomenon, known as the Raman effect,has been well-described in the literature.4143 The inelasticscattering of photons (Raman scattering) is a very rare event.Only one out of 1010 of the incident photons is inelasticallyscattered.43 Nevertheless, these photons provide informationabout molecular vibrations and consequently the structure ofthe analyzed specimen. In NR scattering, the photon is inelas-tically scattered with the lower (Stokes scattering) or higher(anti-Stokes scattering) energies, leaving the molecule in theexcited vibrational state of the electronic ground state (Fig. 1).The same vibrational transition takes place upon resonanceRaman scattering with the only difference that the excitationoccurs with the frequency of the electronic absorption band.In this case, the vibrational modes whose motions are coupledto the driven motion of the electronic transition are primarilyobserved.

    Igor K. Lednev

    Igor K. Lednev is a professor atthe University at Albany, StateUniversity of New York. Hegraduated from the MoscowInstitute of Physics and Technol-ogy with a Ph.D. degree in 1983.He joined the University atAlbany in 2002. His research isfocused on the development ofnovel laser spectroscopy for bio-medical research and forensicpurposes. Lednev served as anadvisory member for the WhiteHouse Subcommittee on Forensic

    Science. He is a Fellow of the Society for Applied Spectroscopy, arecipient of the Research Innovation Award and the University Pre-sident Award for Excellence in Research. Lednev co-authored over160 peer-reviewed publications.

    Critical Review Analyst

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