Editing Amyloid (section)

== Structure ==
[[File:Protofilament of Beta Amyloid.jpg|thumb|Structure of a fibril, consisting of one single protofilament, of the amyloid β peptide viewed down the long axis of the fibril ({{PDB|2mlq}})<ref name="pmid19015532">{{cite journal | vauthors = Paravastu AK, Leapman RD, Yau WM, Tycko R | title = Molecular structural basis for polymorphism in Alzheimer's β-amyloid fibrils | journal = PNAS | volume = 105 | issue = 47 | pages = 18349–54 | date = 25 November 2008 | pmid = 19015532 | doi = 10.1073/pnas.0806270105 | pmc = 2587602 | bibcode = 2008PNAS..10518349P | doi-access = free }}</ref>]]

Amyloids are formed of long unbranched fibers that are characterized by an extended [[β sheet|β-sheet secondary structure]] in which individual [[beta strand|β strand]]s (β-strands) (coloured arrows in the adjacent figure) are arranged in an orientation perpendicular to the long axis of the fiber. Such a structure is known as cross-β structure. Each individual fiber may be 7–13 [[nanometre]]s in width and a few [[micrometre]]s in length.<ref name="ann rev biochem 2011"/><ref name="pmid28498720"/> The main hallmarks recognised by different disciplines to classify protein aggregates as amyloid is the presence of a fibrillar morphology with the expected diameter, detected using [[transmission electron microscopy]] (TEM) or [[atomic force microscopy]] (AFM), the presence of a cross-β secondary structure, determined with [[circular dichroism]], [[Fourier transform infrared spectroscopy|FTIR]], [[solid-state nuclear magnetic resonance]] (ssNMR), [[X-ray crystallography]], or [[X-ray diffraction|X-ray fiber diffraction]] (often considered the "gold-standard" test to see whether a structure contains cross-β fibres), and an ability to stain with specific dyes, such as [[Congo red]], [[thioflavin T]] or [[thioflavin S]].<ref name="pmid28498720"/>

The term "cross-β" was based on the observation of two sets of diffraction lines, one longitudinal and one transverse, that form a characteristic "cross" pattern.<ref>Wormell RL. ''New fibres from proteins''. Academic Press, 1954, p. 106.</ref> There are two characteristic scattering diffraction signals produced at 4.7 and 10&nbsp;[[Ångstrom|Å]] (0.47&nbsp;nm and 1.0&nbsp;nm), corresponding to the interstrand and stacking distances in β sheets.<ref name="pmid9356260"/> The "stacks" of β sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned β-strands. The cross-β pattern is considered a diagnostic hallmark of amyloid structure.<ref name="ann rev biochem 2011"/>

Amyloid fibrils are generally composed of 1–8 protofilaments (one protofilament also corresponding to a fibril is shown in the figure), each 2–7&nbsp;nm in diameter, that interact laterally as flat ribbons that maintain the height of 2–7&nbsp;nm (that of a single protofilament) and are up to 30&nbsp;nm wide; more often protofilaments twist around each other to form the typically 7–13&nbsp;nm wide fibrils.<ref name="pmid28498720"/> Each protofilament possesses the typical cross-β structure and may be formed by 1–6 β-sheets (six are shown in the figure) stacked on each other. Each individual protein molecule can contribute one to several β-strands in each protofilament and the strands can be arranged in antiparallel β-sheets, but more often in parallel β-sheets. Only a fraction of the polypeptide chain is in a β-strand conformation in the fibrils, the remainder forms structured or unstructured loops or tails.

For a long time our knowledge of the atomic-level structure of amyloid fibrils was limited by the fact that they are unsuitable for the most traditional methods for studying protein structures. Recent years have seen progress in experimental methods, including [[solid-state NMR]] spectroscopy and [[cryo-electron microscopy]]. Combined, these methods have provided 3D atomic structures of amyloid fibrils formed by amyloid β peptides, α-synuclein, tau, and the FUS protein, associated with various neurodegenerative diseases.<ref>{{cite journal | vauthors = Meier BH, Riek R, Böckmann A | title = Emerging Structural Understanding of Amyloid Fibrils by Solid-State NMR | journal = Trends in Biochemical Sciences | volume = 42 | issue = 10 | pages = 777–787 | date = October 2017 | pmid = 28916413 | doi = 10.1016/j.tibs.2017.08.001 | hdl = 20.500.11850/193533 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Fitzpatrick AW, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SH | display-authors = 6 | title = Cryo-EM structures of tau filaments from Alzheimer's disease | journal = Nature | volume = 547 | issue = 7662 | pages = 185–190 | date = July 2017 | pmid = 28678775 | pmc = 5552202 | doi = 10.1038/nature23002 | bibcode = 2017Natur.547..185F }}</ref>

[[X-ray crystallography|X-ray diffraction studies of microcrystals]] revealed [[Atomistics|atomistic]] details of core region of amyloid, although only for simplified peptides having a length remarkably shorter than that of peptides or proteins involved in disease.<ref name=Nelson2005>{{cite journal | vauthors = Nelson R, Sawaya MR, Balbirnie M, Madsen AØ, Riekel C, Grothe R, Eisenberg D | title = Structure of the cross-β spine of amyloid-like fibrils | journal = Nature | volume = 435 | issue = 7043 | pages = 773–8 | date = June 2005 | pmid = 15944695 | pmc = 1479801 | doi = 10.1038/nature03680 | bibcode = 2005Natur.435..773N }}</ref><ref name=Sawaya2007>{{cite journal | vauthors = Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJ, McFarlane HT, Madsen AØ, Riekel C, Eisenberg D | display-authors = 6 | title = Atomic structures of amyloid cross-β spines reveal varied steric zippers | journal = Nature | volume = 447 | issue = 7143 | pages = 453–7 | date = May 2007 | pmid = 17468747 | doi = 10.1038/nature05695 | bibcode = 2007Natur.447..453S | s2cid = 4400866 }}</ref> The crystallographic structures show that short stretches from amyloid-prone regions of amyloidogenic proteins run perpendicular to the filament axis, consistent with the "cross-β" feature of amyloid structure. They also reveal a number of characteristics of amyloid structures – neighboring β-sheets are tightly packed together via an interface devoid of water (therefore referred to as dry interface), with the opposing β-strands slightly offset from each other such that their side-chains interdigitate. This compact dehydrated interface created was termed a steric-zipper interface.<ref name="ann rev biochem 2011"/> There are eight theoretical classes of steric-zipper interfaces, dictated by the directionality of the β-sheets (parallel and anti-parallel) and symmetry between adjacent β-sheets. A limitation of X-ray crystallography for solving amyloid structure is represented by the need to form microcrystals, which can be achieved only with peptides shorter than those associated with disease.

Although bona fide amyloid structures always are based on intermolecular β-sheets, different types of "higher order" tertiary folds have been observed or proposed. The β-sheets may form a [[Beta-sandwich|β-sandwich]], or a β-solenoid which may be either [[Beta helix|β-helix]] or β-roll. Native-like amyloid fibrils in which native β-sheet containing proteins maintain their native-like structure in the fibrils have also been proposed.<ref name=PMID12219081>{{cite journal | vauthors = Serag AA, Altenbach C, Gingery M, Hubbell WL, Yeates TO | title = Arrangement of subunits and ordering of β-strands in an amyloid sheet | journal = Nature Structural Biology | volume = 9 | issue = 10 | pages = 734–9 | date = October 2002 | pmid = 12219081 | doi = 10.1038/nsb838 | s2cid = 23926428 }}</ref> There are few developed ideas on how the complex backbone topologies of disulfide-constrained proteins, which are prone to form amyloid fibrils (such as insulin and lysozyme), adopt the amyloid β-sheet motif. The presence of multiple constraints significantly reduces the accessible conformational space, making computational simulations of amyloid structures more feasible.<ref>{{cite journal |last1=Puławski |first1=W |last2=Dzwolak |first2=W |title=Virtual Quasi-2D Intermediates as Building Blocks for Plausible Structural Models of Amyloid Fibrils from Proteins with Complex Topologies: A Case Study of Insulin. |journal=Langmuir |date=7 June 2022 |volume=38 |issue=22 |pages=7024–7034 |doi=10.1021/acs.langmuir.2c00699 |pmid=35617668|pmc=9178918 }}</ref>

One complicating factor in studies of amyloidogenic polypeptides is that identical polypeptides can fold into multiple distinct amyloid conformations.<ref name="ann rev biochem 2011"/> This phenomenon is typically described as ''amyloid polymorphism''.<ref name="pm11076514">{{cite journal | vauthors = Balbach JJ, Ishii Y, Antzutkin ON, Leapman RD, Rizzo NW, Dyda F, Reed J, Tycko R | s2cid = 17232045 | display-authors = 6 | title = Amyloid fibril formation by Aβ16-22, a seven-residue fragment of the Alzheimer's β-amyloid peptide, and structural characterization by solid state NMR | journal = Biochemistry | volume = 39 | issue = 45 | pages = 13748–59 | date = November 2000 | pmid = 11076514 | doi = 10.1021/bi0011330 }}</ref><ref name="pm17056725">{{cite journal | vauthors = Bu Z, Shi Y, Callaway DJ, Tycko R | title = Molecular alignment within β-sheets in Aβ<sub>14-23</sub> fibrils: solid-state NMR experiments and theoretical predictions | journal = Biophysical Journal | volume = 92 | issue = 2 | pages = 594–602 | date = January 2007 | pmid = 17056725 | pmc = 1751388 | doi = 10.1529/biophysj.106.091017 | bibcode = 2007BpJ....92..594B | url = }}</ref><ref name="pm12023906">{{cite journal | vauthors = Tjernberg LO, Tjernberg A, Bark N, Shi Y, Ruzsicska BP, Bu Z, Thyberg J, Callaway DJ | display-authors = 6 | title = Assembling amyloid fibrils from designed structures containing a significant amyloid β-peptide fragment | journal = The Biochemical Journal | volume = 366 | issue = Pt 1 | pages = 343–51 | date = August 2002 | pmid = 12023906 | pmc = 1222771 | doi = 10.1042/BJ20020229 }}</ref> It has notable biological consequences given that it is thought to explain the [[prion]] strain phenomenon.