Amyloid Fibrils And Prefibrillar Aggregates Molecular And Biological Properties Pdf
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- A specific form of prefibrillar aggregates that functions as a precursor of amyloid nucleation
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- Mechanistic Contributions of Biological Cofactors in Islet Amyloid Polypeptide Amyloidogenesis
Alexander J. E-mail: sara. E-mail: tpjk2 cam.
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Type II diabetes mellitus is associated with the deposition of fibrillar aggregates in pancreatic islets. The major protein component of islet amyloids is the glucomodulatory hormone islet amyloid polypeptide IAPP. Islet amyloid fibrils are virtually always associated with several biomolecules, including apolipoprotein E, metals, glycosaminoglycans, and various lipids.
IAPP amyloidogenesis has been originally perceived as a self-assembly homogeneous process in which the inherent aggregation propensity of the peptide and its local concentration constitute the major driving forces to fibrillization.
However, over the last two decades, numerous studies have shown a prominent role of amyloid cofactors in IAPP fibrillogenesis associated with the etiology of type II diabetes. It is increasingly evident that the biochemical microenvironment in which IAPP amyloid formation occurs and the interactions of the polypeptide with various biomolecules not only modulate the rate and extent of aggregation, but could also remodel the amyloidogenesis process as well as the structure, toxicity, and stability of the resulting fibrils.
The causative link between the observed pathophysiology and amyloid formation is now supported by numerous genetic, biochemical, and pharmacological studies [ 1 , 3 — 5 ]. More than 30 human endogenous proteins have been identified as precursors of amyloid fibrils whose deposition is associated with tissue degeneration.
Particularly, fibrils are virtually always associated with nonfibrillar biomolecules, including the serum amyloid P component [ 6 ], apolipoprotein E [ 7 ], collagen [ 8 ], metals [ 9 ], glycosaminoglycans GAGs [ 10 ], and various lipids [ 11 ]. The deposition of amyloid fibrils in the islets of Langerhans of patients afflicted by type II diabetes was originally described at the beginning of last century [ 12 ].
Over the 20th century, it was confirmed that islet hyalinization, that is, tissue degeneration into a classy translucent material, was closely associated with diabetes mellitus, particularly in elderly individuals [ 13 , 14 ]. It is only in that the major component of islet amyloids was identified as a residue peptide, the islet amyloid polypeptide IAPP [ 15 ] or amylin [ 16 ].
This elevated local concentration of IAPP in the islets of Langerhans should, in theory, promote the formation of amyloid.
Nonetheless, although IAPP is expressed in nondiabetic subjects at levels higher than those required to form amyloids in vitro [ 18 ], IAPP rarely deposits in the pancreas of normal individuals [ 19 ]. This suggests that IAPP concentration is not the critical factor contributing to its aggregation and proposes that other elements could play a determinant role in the amyloidogenic process and, accordingly, in the etiology of type II diabetes.
In this review, we will initially describe IAPP structure and normal physiological functions and briefly present its proposed mechanisms of aggregation. As the role of model membranes in IAPP fibrillogenesis has been previously discussed in outstanding reviews [ 20 — 23 ], the present paper will mainly put an emphasis on other factors, such as GAGs and metals.
The primary structure of IAPP has been determined in several mammalian species, including monkey, dog, mouse, and rat Figure 1 a. The N- and C-terminal regions of IAPP have been well conserved in all mammalian species, whereas the central 21—29 domain is more variable and shows important interspecies variations. Particularly, IAPP sequences found in mice and rat contain Pro residues at positions 25, 28, and 29 whereas the human sequence encompasses Ala, Ser, and Ser, respectively [ 26 ].
This variation is significant for the amyloidogenesis process, as rat rIAPP and mice mIAPP peptide are less prone to aggregation and these two species do not form islet amyloids [ 27 ]. In solution, human IAPP hIAPP exhibits a conformational ensemble mainly populated by disordered conformations, although it diverges from an absolute random coil by the presence of local and transient ordered structures [ 28 ].
For example, in dodecylphosphocholine DPC micelles, rIAPP exhibits a structure characterized by a single helical region spanning from residues Ala-5 to Ser followed by a disordered C-terminal domain [ 31 ].
Both rat and human 1—19 IAPP fragments show a helical conformation in DPC micelles, although they adopt different orientation on the micelle surface [ 33 ]. IAPP is a member of the calcitonin peptide family, which includes calcitonin, calcitonin-gene-related peptides CGRPs , and adrenomedullin [ 34 ].
These peptide hormones mediate their biological activities by binding and activating class B G protein-coupled receptors GPCRs [ 35 ]. The function, pharmacology, and selectivity of the CT receptor are altered by its association with receptor activity-modifying proteins RAMPs.
IAPP specific binding sites were initially identified in the brain and the renal cortex and have now been identified in several peripheral tissues [ 38 ]. In skeletal muscles, IAPP inhibits basal and insulin-stimulated glycogen synthesis, resulting in an increase of glucosephosphate level [ 25 ]. Studies have also shown that IAPP suppresses glucagon secretion, decreases gastric emptying, and induces satiety [ 25 , 39 , 40 ]. IAPP may also be involved in the process of tissues calcification and could play a critical role in the inhibition of bone resorption [ 41 ].
Like other members of the calcitonin family, IAPP is a potent vasodilator and causes systemic hypotension and tachycardia [ 25 , 42 ]. Taken together, the biological functions of IAPP are still far from being clearly understood [ 25 ]. This structural motif provides the most favorable organization for these supramolecular assemblies and can accommodate a high diversity of polypeptide sequences [ 45 ]. Amyloids are characterized by an X-ray diffraction pattern with two characteristic signals, a clear reflection at 4.
By atomic force microscopy AFM and electron microscopy EM , amyloids extracted from patients or prepared in vitro appear as long 0. Until recently, the structure of amyloids at the atomic level was unclear, since amyloids do not form crystals and are insoluble, precluding their characterization by X-ray crystallography and solution nuclear magnetic resonance NMR. Thanks to recent advances in techniques such as solid state NMR [ 44 ] and the ability of growing nanocrystals of peptide fragments [ 46 ], it has been possible to elucidate the structure of several amyloids.
These approaches, along with cryoelectron microscopy, have suggested that amyloid fibrils present a core sharing several characteristics. Nonetheless, it has also been reported that amyloids have significant structural differences [ 44 ]. Thus, although amyloid fibrils display similar characteristics, a marked polymorphism exists not only between fibrils from different precursors, but also between amyloids assembled from the same polypeptide but in different conditions [ 47 ].
Firstly, in the model derived from solid state NMR study, IAPP protofibrils consist of two columns of symmetry related monomers packed against each other [ 48 ]. Structural analysis of IAPP fibrils was so far exclusively performed using homogenous peptide assemblies, although amyloid deposits in islets of Langerhans of diabetic patients contain a variety of biomolecules, including GAGs, lipids, and other proteins. Thus, it will be interesting to study the molecular architecture of IAPP amyloids assembled in a biologically relevant heterogeneous environment.
While the mechanism by which proteins self-assemble into amyloids has been intensively studied over the last two decades, mechanistic details remain partially elusive and still the matter of controversy.
Amyloidogenic polypeptides can be divided into two different structural classes: those that are intrinsically or partially disordered in their native state and those that show a well-defined tertiary structure in their monomeric soluble state. The formation of amyloid fibrils is often described as a nucleation-dependent polymerization, although other models have been suggested [ 52 ], including the nucleated conformational conversion [ 53 ] and the monomer-directed conversion [ 54 ].
The nucleated polymerization model is characterized by the rate-limiting formation of the nucleus, which results from the equilibrium between monomers that are and are not assembly competent [ 52 ]. As soon as the nucleus is formed, assembly rapidly occurs by the addition of competent monomers to the growing end of the protofibrils. This model is characterized by two well-defined kinetics phases. Firstly, a low amount of dynamic and transient oligomeric species is produced in the lag phase.
This phase takes place slowly because of the unfavorable interactions between monomers to form oligomers. Secondly, once the nucleus competent oligomer is formed, the elongation phase begins, leading to the rapid growth of the bio polymers [ 55 ]. Amyloid formation kinetics, seeding experiments as well as the difficulty of detecting low ordered oligomers [ 23 ], suggest that IAPP amyloidogenesis could be ascribed to a nucleated polymerization. Recent studies performed with different amyloidogenic proteins have suggested that oligomers could be the most proteotoxic species of the aggregation cascade [ 56 — 58 ].
This hypothesis has prompted the biophysical investigation of the early steps in protein aggregation. Besides, the presence of a low percentage of HFIP, a solvent known to promote helical formation, in the aggregation solution of IAPP accelerates the rate of amyloid formation [ 62 , 63 ]. According to the helical intermediates hypothesis, self-association would be thermodynamically associated with helix formation within the 5—20 segment, in a similar way of the driven forces of coiled-coil motif formation [ 59 ].
Taking into account this model, several molecules have been recently designed to target and stabilize helical intermediates with the ultimate goal of inhibiting IAPP amyloid formation [ 65 — 68 ].
The discrepancy between these two models indicates that the initial events of IAPP amyloidogenesis still remain unclear. It is worth mentioning that in contrast to in vitro homogenous aqueous solution, the mechanisms of amyloid formation in vivo are most likely to be different and could involve alternative pathways. IAPP amyloidogenesis takes place in a heterogeneous and crowded environment with the potential interactions with several components of the extracellular matrix and the plasma membrane.
Thus, mechanistic examinations of amyloid formation in heterogeneous environments constitute an important issue and relevant studies will now be discussed. Amyloid formation has been originally perceived as a self-assembly homogeneous process in which the inherent physicochemical and structural properties of the amyloidogenic proteic precursor as well as its concentration constitute the major driving forces to fibrillation. However, numerous biophysical investigations as well as in vivo biochemical studies have shown a prominent role of these extrinsic factors in amyloid deposition associated with the etiology of various diseases, including type II diabetes [ 1 , 8 , 9 ].
It is now evident that the biochemical microenvironment in which amyloid formation occurs and the interactions of the polypeptide precursor with various biomolecules not only modulate the rate and extent of aggregation, but also remodel the mechanisms as well as the structure, toxicity and stability of the resulting fibrils.
Immunohistochemical analysis revealed that the basement membrane heparan sulfate proteoglycan HSPG , perlecan, was present within islet amyloid deposits, suggesting a causative role of sulfated GAGs in IAPP fibrillogenesis [ 69 ]. Similarly, the Westermark group has established a mouse strain that overexpresses both hIAPP and heparanase, an enzyme that catalyzes the cleavage of cell surface heparan sulfate. They reported that isolated islets from these mice showed a marked reduction in amyloid accumulation upon a 2-week high glucose treatment; these conditions simulate the hyperglycemia observed in type II diabetes and stimulate IAPP expression and secretion [ 71 ].
In addition, since the original work by Castillo et al. Overall, these studies constitute a clear testimony that sulfated GAGs could play an active role in islet amyloid deposition associated with type II diabetes.
GAGs are long and linear polysaccharides composed of repeating disaccharide units and some GAGs can contain up to repeating disaccharide units [ 78 ].
They are abundant on the outer leaflet of the plasma membrane of every cell type of metazoan organisms and in their basement membrane and extracellular matrix ECM [ 79 ]. According to the structure of their carbohydrate backbone, GAGs can be classified into several classes. Other types of GAGs include heparin, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid.
Owing to their high density of carboxylate and sulfate groups, GAGs are highly negatively charged biopolymers that constitute a major reservoir of polyanions surrounding cells. With exception of hyaluronic acid and heparin, GAGs are usually covalently O-linked to a protein core, forming a structure known as proteoglycans. Over the last 15 years, several studies have demonstrated that the addition of sulfated GAGs to amyloidogenic proteins accelerates their fibrillogenesis in vitro.
It has been proposed that GAGs hasten amyloidogenesis by a scaffold-based mechanism, in which the amyloidogenic protein, either in its monomeric or oligomeric form, interacts with the sulfated polysaccharides mainly through electrostatic interactions, increasing its local concentration and promoting aggregation [ 85 , 86 , 88 ]. However, this structural modification is most likely related to the aggregation process rather than to a conformational conversion within the monomeric protein.
The mechanisms by which sulfated GAGs accelerate IAPP amyloid formation have been studied by a combination of biophysical approaches and are similar to the one described for other amyloidogenic polypeptides.
Besides, it was reported by isothermal titration calorimetry ITC that the affinity of IAPP to sulfated GAGs was dependent on the protonation state of His and that the binding was predominately enthalpy-driven, most related to electrostatic interactions [ 75 ]. A heparin binding site was characterized within the N-terminal domain of proIAPP [ 77 , 90 ] and it was suggested that the interaction of unprocessed proIAPP with sulfated GAGs could have strong implications for amyloid formation in pancreatic islets.
As the binding of IAPP and proIAPP accelerates the rate of amyloid formation, this secondary conformational conversion supports the helical intermediates hypothesis described above. Several reports have suggested that the dysregulation of metal ion homeostasis could be implicated in the pathogenesis of amyloid diseases, comprising type II diabetes [ 9 ].
While it is known for more than 20 years that the secretory granules in pancreatic islets of Langerhans, which store IAPP and insulin, are characterized by a high concentration of zinc [ 97 ], the role of this metal in IAPP amyloidogenesis has not been addressed until recently [ 98 , 99 ].
The modulation of IAPP amyloidogenesis in vitro by zinc is complex and is dependent on zinc concentration as well as the pH and peptide concentration [ 98 ]. At pH 7. It was also observed that while the total amount of fibrils is greatly reduced by zinc at all concentrations, the general morphology of the individual fibrils remained somewhat similar [ 98 ].
In sharp contrast, at pH 5. Brender and colleagues have observed that IAPP in an organic solvent undergoes a structural conversion upon zinc binding characterized by a local disruption of the helical structure around residue His [ 98 ].
Thus, the inhibitory effect of zinc observed at low concentrations was initially ascribed to the unfavorable incorporation of a charge inside the loops [ 98 ], as the imidazole ring of His is located in the hydrophobic core of the fiber [ 48 ]. By combining ITC, NMR, and ESI mass spectrometry, it was observed that zinc favors the formation of off-pathway hexameric species while creating an energetic barrier for the formation of amyloids [ ].
Thus, zinc binding to nonfibrillar IAPP with an affinity in the micromolar range [ ] promotes the formation of prefibrillar aggregates [ 99 ], ultimately inhibiting the formation of amyloid fibrils. The effect of the buffer ion composition on the kinetics of IAPP amyloid formation was recently examined and it was reported that IAPP fibrillogenesis was dependent on the anion identity, while the nature of the cationic species has little effect on the rate of fibrils formation [ ].
Particularly, it will be interesting to probe the effects of zinc and copper on the kinetics of IAPP self-assembly in heterogeneous environment, that is, in presence of other biological factors such as GAGs and lipid membrane models. Virtually all amyloid deposits, including islet amyloids [ , ], are associated with apolipoprotein E apoE , a protein involved in lipid transport and metabolism.
In sharp contrast, transgenic mice expressing hIAPP crossbred with apoE deficient mice showed similar prevalence and severity of islet amyloids, indicating that apoE is not a critical factor for islet amyloid deposition [ ].
The postulated mechanism of fibrillogenesis inhibition by insulin is consistent with the helical intermediates hypothesis.
A specific form of prefibrillar aggregates that functions as a precursor of amyloid nucleation
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Such amyloids have been associated with but not necessarily as the cause of more than 50   human diseases, known as amyloidosis , and may play a role in some neurodegenerative disorders. Others are only familial. Some are iatrogenic as they result from medical treatment. One amyloid protein is infectious and is called prion in which the infectious form can act as a template to convert other non-infectious proteins into infectious form. Amyloids have been known to arise from many different proteins.
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There is an ongoing debate regarding the culprits of cytotoxicity associated with amyloid disorders. Although small pre-fibrillar amyloid oligomers have been implicated as the primary toxic species, the fibrillar amyloid material itself can also induce cytotoxicity. To investigate membrane disruption and cytotoxic effects associated with intact and fragmented fibrils, the novel in situ spectroscopic technique of Total Internal Reflection Ellipsometry TIRE was used. Fibril lipid interactions were monitored using natively derived whole cell membranes as a model of the in vivo environment. We show that fragmented fibrils have an increased ability to disrupt these natively derived membranes by causing a loss of material from the deposited surface when compared with unfragmented fibrils.
Type II diabetes mellitus is associated with the deposition of fibrillar aggregates in pancreatic islets. The major protein component of islet amyloids is the glucomodulatory hormone islet amyloid polypeptide IAPP. Islet amyloid fibrils are virtually always associated with several biomolecules, including apolipoprotein E, metals, glycosaminoglycans, and various lipids. IAPP amyloidogenesis has been originally perceived as a self-assembly homogeneous process in which the inherent aggregation propensity of the peptide and its local concentration constitute the major driving forces to fibrillization. However, over the last two decades, numerous studies have shown a prominent role of amyloid cofactors in IAPP fibrillogenesis associated with the etiology of type II diabetes.
Mechanistic Contributions of Biological Cofactors in Islet Amyloid Polypeptide Amyloidogenesis
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Amyloid Fibrils and Prefibrillar Aggregates: Molecular and Biological Properties. Editor(s). Prof. Dr. Daniel Erik Otzen. First published