Site-specific detection of protein secondary structure using 2D IR dihedral indexing: a proposed assembly mechanism of oligomeric hIAPP
TLDR
Human islet amyloid polypeptide (hIAPP) aggregates into fibrils through oligomers that have been postulated to contain α-helices as well as β-sheets.Abstract:
Human islet amyloid polypeptide (hIAPP) aggregates into fibrils through oligomers that have been postulated to contain α-helices as well as β-sheets. We employ a site-specific isotope labeling strategy that is capable of detecting changes in dihedral angles when used in conjunction with 2D IR spectroscopy. The method is analogous to the chemical shift index used in NMR spectroscopy for assigning protein secondary structure. We introduce isotope labels at two neighbouring residues, which results in an increased intensity and positive frequency shift if those residues are α-helical versus a negative frequency shift in β-sheets and turns. The 2D IR dihedral index approach is demonstrated for hIAPP in micelles for which the polypeptide structure is known, using pairs of 13C18O isotope labels L12A13 and L16V17, along with single labeled control experiments. Applying the approach to aggregation experiments performed in buffer, we show that about 27–38% of hIAPP peptides adopt an α-helix secondary structure in the monomeric state at L12A13, prior to aggregation, but not at L16V17 residues. At L16V17, the kinetics are described solely by the monomer and fiber conformations, but at L12A13 the kinetics exhibit a third state that is created by an oligomeric intermediate. Control experiments performed with a single isotope label at A13 exhibit two-state kinetics, indicating that a previously unknown change in dihedral angle occurs at L12A13 as hIAPP transitions from the intermediate to fiber structures. We propose a mechanism for aggregation, in which helices seed oligomer formation via structures analogous to leucine rich repeat proteins.read more
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Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes
Danilo Milardi,Ehud Gazit,Sheena E. Radford,Yong Xu,Rodrigo Gallardo,Amedeo Caflisch,Gunilla T. Westermark,Per Westermark,Carmelo La Rosa,Ayyalusamy Ramamoorthy +9 more
TL;DR: A review of the current knowledge of the structures and pathology associated with hIAPP self-assembly and point out the opportunities for therapy that a detailed biochemical, biophysical, and cellular understanding of its aggregation may unveil.
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Graphene quantum dots against human IAPP aggregation and toxicity in vivo.
Miaoyi Wang,Yunxiang Sun,Xueying Cao,Guotao Peng,Ibrahim Javed,Aleksandr Kakinen,Thomas P. Davis,Sijie Lin,Jingquan Liu,Feng Ding,Pu Chun Ke +10 more
TL;DR: GQDs initiated contact with IAPP through electrostatic and hydrophobic interactions as well as hydrogen bonding, which subsequently drove the peptide fibrillization off-pathway to eliminate the toxic intermediates.
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Two-Dimensional Spectroscopy Is Being Used to Address Core Scientific Questions in Biology and Materials Science
TL;DR: The ways in which two-dimensional visible and infrared spectroscopies are being applied to elucidate fundamental details of important processes in biological and materials science are provided.
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Vibrational Approach to the Dynamics and Structure of Protein Amyloids
TL;DR: This work addresses the application of the vibrational approaches in recent studies of conformational dynamics and structural characteristics of protein oligomers and amyloid fibrils, and discusses how introduction of isotope labelled carbonyl into a peptide backbone, and incorporation of the extrinsic unnatural amino acids with vibrational moieties on the side chain have greatly expanded the ability of vibrational spectroscopy.
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Amyloid Self-Assembly of hIAPP8-20 via the Accumulation of Helical Oligomers, α-Helix to β-Sheet Transition, and Formation of β-Barrel Intermediates.
Yunxiang Sun,Yunxiang Sun,Aleksandr Kakinen,Yanting Xing,Pouya Faridi,Aparna Nandakumar,Anthony W. Purcell,Thomas P. Davis,Pu Chun Ke,Feng Ding +9 more
TL;DR: A complete picture is uncovered of hIAPP8-20 peptide oligomerization, aggregation nucleation via conformational conversion, formation of β-barrel intermediates, and assembly of cross-β protofibrils, thereby shedding light on the aggregation of full-length hI APP, a hallmark of pancreatic beta-cell degeneration.
References
More filters
Journal ArticleDOI
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
Rakez Kayed,Elizabeth Head,Jennifer L. Thompson,Theresa M. McIntire,Saskia Milton,Carl W. Cotman,Charles G. Glabe +6 more
TL;DR: It is shown that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomer regardless of sequence, suggesting they share a common mechanism of toxicity.
Journal ArticleDOI
National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants
Goodarz Danaei,Mariel M. Finucane,Yuan Lu,Gitanjali M Singh,Melanie J. Cowan,Christopher J. Paciorek,Christopher J. Paciorek,John K Lin,Farshad Farzadfar,Young-Ho Khang,Gretchen A Stevens,Mayuree Rao,Mohammed K. Ali,Leanne M Riley,Carolyn Robinson,Majid Ezzati +15 more
TL;DR: Glycaemia and diabetes are rising globally, driven both by population growth and ageing and by increasing age-specific prevalences, and effective preventive interventions are needed, and health systems should prepare to detect and manage diabetes and its sequelae.
Journal ArticleDOI
The chemical shift index: A fast and simple method for the assignment of protein secondary structure through NMR spectroscopy
TL;DR: This new method for rapidly and quantitatively determining the identity, extent, and location of secondary structural elements in proteins based on the simple inspection of the alpha-CH 1H resonance assignments is found to be almost as accurate as the more traditional NOE-based methods of determining secondary structure.
Journal ArticleDOI
Algorithms and applications for approximate nonnegative matrix factorization
TL;DR: The development and use of low-rank approximate nonnegative matrix factorization algorithms for feature extraction and identification in the fields of text mining and spectral data analysis and the interpretability of NMF outputs in specific contexts are provided.
Journal ArticleDOI
Structure of the amide i band of peptides measured by femtosecond nonlinear-infrared spectroscopy
TL;DR: In this paper, a femtosecond pump probe and dynamic hole burning experiments were used to examine the ultrafast response of the modes in the 1600−1700 cm-1 region (the so-called amide I modes) of N-methylacetamide (NMA) and three small globular peptides, apamin, scyllatoxin, and bovine pancreatic trypsin inhibitor (BPTI).