RESUMEN
Amyloid fibrils (AFs) are highly ordered protein nanofibers composed of cross ß-structure that occur in nature, but that also accumulate in age-related diseases. Amyloid propensity is a generic property of proteins revealed by conditions that destabilize the native state, suggesting that food processing conditions may promote AF formation. This had only been shown for foie gras, but not in common foodstuffs. We here extracted a dense network of fibrillar proteins from commonly consumed boiled hen egg white (EW) using chemical and/or enzymatic treatments. Conversion of EW proteins into AFs during boiling was demonstrated by thioflavin T fluorescence, Congo red staining, and X-ray fiber diffraction measurements. Our data show that cooking converts approximately 1-3% of the protein in EW into AFs, suggesting that they are a common component of the human diet.
Asunto(s)
Amiloide , Amiloidosis , Proteínas Amiloidogénicas , Proteínas del Huevo , Clara de Huevo , HumanosRESUMEN
Human apolipoprotein E (apoE) is a major component of lipoprotein particles, and under physiological conditions, is involved in plasma cholesterol transport. Human apolipoprotein E found in three isoforms (E2; E3; E4) is a member of a family of apolipoproteins that under pathological conditions are detected in extracellular amyloid depositions in several amyloidoses. Interestingly, the lipid-free apoE form has been shown to be co-localized with the amyloidogenic Aß peptide in amyloid plaques in Alzheimer's disease, whereas in particular, the apoE4 isoform is a crucial risk factor for late-onset Alzheimer's disease. Evidence at the experimental level proves that apoE self-assembles into amyloid fibrilsin vitro, although the misfolding mechanism has not been clarified yet. Here, we explored the mechanistic insights of apoE misfolding by testing short apoE stretches predicted as amyloidogenic determinants by AMYLPRED, and we computationally investigated the dynamics of apoE and an apoE-Αß complex. Our in vitro biophysical results prove that apoE peptide-analogues may act as the driving force needed to trigger apoE aggregation and are supported by the computational apoE outcome. Additional computational work concerning the apoE-Αß complex also designates apoE amyloidogenic regions as important binding sites for oligomeric Αß; taking an important step forward in the field of Alzheimer's anti-aggregation drug development.
Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/química , Amiloidosis/genética , Apolipoproteínas E/química , Enfermedad de Alzheimer/patología , Amiloide/química , Amiloide/genética , Amiloide/ultraestructura , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/ultraestructura , Amiloidosis/patología , Apolipoproteínas E/ultraestructura , Sitios de Unión , Colesterol/química , Colesterol/genética , Humanos , Placa Amiloide/genética , Placa Amiloide/patología , Placa Amiloide/ultraestructura , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/patología , Pliegue de Proteína , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/ultraestructuraRESUMEN
The Calcitonin-gene related peptide (CGRP) family is a group of peptide hormones, which consists of IAPP, calcitonin, adrenomedullin, intermedin, αCGRP and ßCGRP. IAPP and calcitonin have been extensively associated with the formation of amyloid fibrils, causing Type 2 Diabetes and Medullary Thyroid Carcinoma, respectively. In contrast, the potential amyloidogenic properties of αCGRP still remain unexplored, although experimental trials have indicated its presence in deposits, associated with the aforementioned disorders. Therefore, in this work, we investigated the amyloidogenic profile of αCGRP, a 37-residue-long peptide hormone, utilizing both biophysical experimental techniques and Molecular Dynamics simulations. These efforts unravel a novel amyloidogenic member of the CGRP family and provide insights into the mechanism underlying the αCGRP polymerization.
Asunto(s)
Proteínas Amiloidogénicas/química , Péptido Relacionado con Gen de Calcitonina/química , Proteínas Amiloidogénicas/fisiología , Péptido Relacionado con Gen de Calcitonina/fisiología , Humanos , Simulación de Dinámica Molecular , Difracción de Rayos XRESUMEN
Human islet amyloid polypeptide (hIAPP) is the major protein component of extracellular amyloid deposits, located in the islets of Langerhans, a hallmark of type II diabetes. The underlying mechanisms of IAPP aggregation have not yet been clearly defined, although the highly amyloidogenic sequence of the protein has been extensively studied. Several segments have been highlighted as aggregation-prone regions (APRs), with much attention focused on the central 8-17 and 20-29 stretches. In this work, we employ micro-Raman spectroscopy to identify specific regions that are contributing to or are excluded from the amyloidogenic core of IAPP amyloid fibrils. Our results demonstrate that both the N-terminal region containing a conserved disulfide bond between Cys residues at positions 2 and 7, and the C-terminal region containing the only Tyr residue are excluded from the amyloid core. Finally, by performing detailed aggregation assays and molecular dynamics simulations on a number of IAPP variants, we demonstrate that point mutations within the central APRs contribute to the reduction of the overall amyloidogenic potential of the protein but do not completely abolish the formation of IAPP amyloid fibrils.
Asunto(s)
Amiloide/química , Diabetes Mellitus Tipo 2/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/química , Variación Genética , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/genética , Simulación de Dinámica Molecular , Mutación , Espectrometría Raman/métodosRESUMEN
Over the last 20 years, proinsulin C-peptide emerged as an important player in various biological events. Much time and effort has been spent in exploring all functional features of C-peptide and recording its implications in Diabetes mellitus. Only a few studies, though, have addressed C-peptide oligomerization and link this procedure with Diabetes. The aim of our work was to examine the aggregation propensity of C-peptide, utilizing Transmission Electron Microscopy, Congo Red staining, ATR-FTIR, and X-ray fiber diffraction at a 10 mg ml-1 concentration. Our experimental work clearly shows that C-peptide self-assembles into amyloid-like fibrils and therefore, the aggregation propensity of C-peptide is a characteristic novel feature that should be related to physiological and also pathological conditions. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 108: 1-8, 2017.
Asunto(s)
Péptido C/química , Insulina/química , Agregación Patológica de Proteínas , Conformación Proteica , Secuencia de Aminoácidos , Amiloide/química , Amiloide/metabolismo , Péptido C/metabolismo , Péptido C/ultraestructura , Rojo Congo/química , Diabetes Mellitus/metabolismo , Humanos , Insulina/metabolismo , Microscopía Electrónica de Transmisión , Microscopía de Polarización , Microscopía por Video , Multimerización de Proteína , Espectroscopía Infrarroja por Transformada de Fourier , Coloración y Etiquetado/métodos , Difracción de Rayos XRESUMEN
Clusterin, a multitasking glycoprotein, is a protein highly conserved amongst mammals. In humans, Clusterin is mainly a secreted protein, described as an extracellular chaperone with the capability of interacting with a broad spectrum of molecules. In neurodegenerative diseases, such as Alzheimer's disease, it is an amyloid associated protein, co-localized with fibrillar deposits in amyloid plaques in systemic or localized amyloidoses. An 'aggregation-prone' segment (NFHAMFQ) was located within the Clusterin α-chain sequence using AMYLPRED, a consensus method for the prediction of amyloid propensity, developed in our lab. This peptide was synthesized and was found to self-assemble into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, Attenuated Total Reflectance Fourier-Transform Spectroscopy and Congo red staining studies reveal. All experimental results verify that this human Clusterin peptide-analogue, possesses high aggregation potency. Additional computational analysis highlighted novel and at the same time, unexplored features of human Clusterin.
Asunto(s)
Amiloidosis , Clusterina/química , Biología Computacional , Amiloide , Animales , Humanos , Conformación ProteicaRESUMEN
Several organisms exploit the extraordinary physical properties of amyloid fibrils forming natural protective amyloids, in an effort to support complex biological functions. Curli amyloid fibers are a major component of mature biofilms, which are produced by many Enterobacteriaceae species and are responsible, among other functions, for the initial adhesion of bacteria to surfaces or cells. The main axis of curli fibers is formed by a major structural subunit, known as CsgA. CsgA self-assembly is promoted by oligomeric nuclei formed by a minor curli subunit, known as the CsgB nucleator protein. Here, by implementing AMYLPRED2, a consensus prediction method for the identification of 'aggregation-prone' regions in protein sequences, developed in our laboratory, we have successfully identified potent amyloidogenic regions of the CsgB subunit. Peptide-analogues corresponding to the predicted 'aggregation-prone' segments of CsgB were chemically synthesized and studied, utilizing several biophysical techniques. Our experimental data indicate that these peptides self-assemble in solution, forming fibrils with characteristic amyloidogenic properties. Using comparative modeling techniques, we have developed three-dimensional models of both CsgA and CsgB subunits. Structural analysis revealed that the identified 'aggregation-prone' segments may promote gradual polymerization of CsgB. Briefly, our results indicate that the intrinsic self-aggregation propensity of the CsgB subunit, most probably has a pivotal role in initiating the formation of curli amyloid fibers by promoting the self-assembly process of the CsgB nucleator protein.
Asunto(s)
Amiloide/química , Proteínas de Escherichia coli/química , Secuencia de Aminoácidos/genética , Amiloide/ultraestructura , Biopelículas , Fenómenos Biofísicos , Escherichia coli/química , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/ultraestructura , Péptidos/síntesis química , Péptidos/química , Polimerizacion , Agregado de Proteínas/genéticaRESUMEN
Pmel17 is the major component of functional amyloid fibrils that have an important role during pigment deposition. Pmel17 polymerization is promoted within the mildly acidic conditions of melanosomes, organelles located in pigment-specific cells. A repeat domain (RPT domain) of Pmel17, rich in glutamic acid residues has been extensively associated with the formation of the fibrous matrix. Here, we examine the RPT domain of human Pmel17 in order to provide information on this mechanism. Specifically, we have identified an aggregation-prone peptide segment ((405) VSIVVLSGT(413) ), close to the C-terminal part of the RPT domain. Experimental results utilizing electron microscopy, X-ray fiber diffraction, Congo red staining and ATR FT-IR spectroscopy indicate that this peptide segment self-assembles forming fibrils with evident amyloidogenic properties. Conclusively, our results demonstrate that the (405) VSIVVLSGT(413) peptide segment possibly has an essential role in RPT domain fibrillogenesis.
Asunto(s)
Amiloide/química , Antígeno gp100 del Melanoma/química , Humanos , Microscopía Electrónica de Transmisión , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
Pmel17 is a multidomain protein involved in biosynthesis of melanin. This process is facilitated by the formation of Pmel17 amyloid fibrils that serve as a scaffold, important for pigment deposition in melanosomes. A specific luminal domain of human Pmel17, containing 10 tandem imperfect repeats, designated as repeat domain (RPT), forms amyloid fibrils in a pH-controlled mechanism in vitro and has been proposed to be essential for the formation of the fibrillar matrix. Currently, no three-dimensional structure has been resolved for the RPT domain of Pmel17. Here, we examine the structure of the RPT domain by performing sequence threading. The resulting model was subjected to energy minimization and validated through extensive molecular dynamics simulations. Structural analysis indicated that the RPT model exhibits several distinct properties of ß-solenoid structures, which have been proposed to be polymerizing components of amyloid fibrils. The derived model is stabilized by an extensive network of hydrogen bonds generated by stacking of highly conserved polar residues of the RPT domain. Furthermore, the key role of invariant glutamate residues is proposed, supporting a pH-dependent mechanism for RPT domain assembly. Conclusively, our work attempts to provide structural insights into the RPT domain structure and to elucidate its contribution to Pmel17 amyloid fibril formation.
Asunto(s)
Amiloide/química , Melanosomas/química , Secuencias Repetitivas de Aminoácido/genética , Antígeno gp100 del Melanoma/química , Humanos , Melanosomas/genética , Conformación Proteica , Dominios Proteicos , Estructura Terciaria de Proteína , Antígeno gp100 del Melanoma/genéticaRESUMEN
Amyloidogenic proteins like human Cystatin C (hCC) have been shown to form dimers and oligomers by exchange of subdomains of the monomeric proteins. Normally, the hCC monomer, a low molecular type 2 Cystatin, consists of 120 amino acid residues and functions as an inhibitor of cysteine proteases. The oligomerization of hCC is involved in the pathophysiology of a rare form of amyloidosis namely Icelandic hereditary cerebral amyloid angiopathy, in which an L68Q mutant is deposited as amyloid in brain arteries of young adults. In order to find the shortest stretch responsible to drive the fibril formation of hCC, we have previously demonstrated that the LQVVR peptide forms amyloid fibrils, in vitro (Tsiolaki et al., 2015). Predictions by AMYLPRED, an amyloidogenic determinant prediction algorithm developed in our lab, led us to synthesize and experimentally study two additional predicted peptides derived from hCC. Along with our previous findings, in this work, we reveal that these peptides self-assemble, in a similar way, into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy and Congo red staining studies have shown. Further to our experimental results, all three peptides seem to have a fundamental contribution in forming the "aggregation-prone" core of human Cystatin C.
Asunto(s)
Cistatina C/química , Secuencia de Aminoácidos , Amiloide/química , Amiloidosis/genética , Dimerización , Humanos , Microscopía Electrónica/métodos , Datos de Secuencia Molecular , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Difracción de Rayos X/métodosRESUMEN
Amyloid deposits to the islets of Langerhans are responsible for the gradual loss of pancreatic ß-cells leading to type II diabetes mellitus. Human mature islet amyloid polypeptide (hIAPP), a 37-residue pancreatic hormone, has been identified as the primary component of amyloid fibrils forming these deposits. Several individual segments along the entire sequence length of hIAPP have been nominated as regions with increased amyloidogenic potential, such as regions 8-20, 20-29, and 30-37. A smaller fragment of the 8-20 region, spanning residues 8-16 of hIAPP has been associated with the formation of early transient α-helical dimers that promote fibrillogenesis and also as a core part of hIAPP amyloid fibrils. Utilizing our aggregation propensity prediction tools AmylPred and AmylPred2, we have identified the high aggregation propensity of the 8-16 segment of hIAPP. A peptide analog corresponding to this segment was chemically synthesized and its amyloidogenic properties were validated using electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy, and polarized microscopy. Additionally, two peptides introducing point mutations L12R and L12P, respectively, to the 8-16 segment, were chemically synthesized. Both mutations disrupt the α-helical properties of the 8-16 region and lower its amyloidogenic potential, which was confirmed experimentally. Finally, cytotoxicity assays indicate that the 8-16 segment of hIAPP shows enhanced cytotoxicity, which is relieved by the L12R mutation but not by the L12P mutation. Our results indicate that the chameleon properties and the high aggregation propensity of the 8-16 region may significantly contribute to the formation of amyloid fibrils and the overall cytotoxic effect of hIAPP.
Asunto(s)
Citotoxinas , Polipéptido Amiloide de los Islotes Pancreáticos , Péptidos , Agregado de Proteínas , Línea Celular , Citotoxinas/síntesis química , Citotoxinas/química , Citotoxinas/farmacología , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/química , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacologíaRESUMEN
Egg envelopes of vertebrates are composed of a family of proteins called zona pellucida (ZP) proteins, which are distinguished by the presence of a common structural polymerizing motif, known as ZP domain. Teleostean fish chorion is a fibrous structure, consisting of protein members of the ZPB/ZP1 and the ZPC/ZP3 families, which are incorporated as tandemly repeating heterodimers inside chorion fibers. Computational analysis of multiple ZPB/ZP1 proteins from several teleostean species, reveals two potential "aggregation-prone" sequence segments, forming a specific polymerization interface (AG interface). These two peptides were synthesized and results are presented in this work from transmission electron microscopy, Congo red staining, X-ray fiber diffraction and ATR FT-IR, which clearly display the ability of these peptides to self-aggregate, forming amyloid-like fibrils. This, most probably implies that the AG interface of ZPB/ZP1 proteins plays an important role for the formation of the repeating ZPB-ZPC heterodimers, which constitute teleostean chorion fibrils.
Asunto(s)
Proteínas del Huevo/química , Proteínas de Peces/química , Óvulo/química , Péptidos/química , Agregado de Proteínas , Secuencia de Aminoácidos , Amiloide/química , Amiloide/ultraestructura , Animales , Secuencia de Consenso , Modelos Moleculares , Datos de Secuencia Molecular , Multimerización de Proteína , Alineación de Secuencia , Espectroscopía Infrarroja por Transformada de Fourier , Homología Estructural de Proteína , Difracción de Rayos X , Zona Pelúcida/químicaRESUMEN
Functional bacterial amyloid provides structural stability in biofilm, making it a promising target for anti-biofilm therapeutics. Fibrils formed by CsgA, the major amyloid component in E. coli are extremely robust and can withstand very harsh conditions. Like other functional amyloids, CsgA contains relatively short aggregation-prone regions (APR) which drive amyloid formation. Here, we demonstrate the use of aggregation-modulating peptides to knock down CsgA protein into aggregates with low stability and altered morphology. Remarkably, these CsgA-peptides also modulate fibrillation of the unrelated functional amyloid protein FapC from Pseudomonas, possibly through recognition of FapC segments with structural and sequence similarity with CsgA. The peptides also reduce the level of biofilm formation in E. coli and P. aeruginosa, demonstrating the potential for selective amyloid targeting to combat bacterial biofilm.
Asunto(s)
Amiloide , Proteínas Bacterianas , Biopelículas , Proteínas de Escherichia coli , Escherichia coli , Péptidos , Agregado de Proteínas , Amiloide/química , Proteínas Amiloidogénicas/química , Proteínas Bacterianas/química , Biopelículas/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/química , Péptidos/química , Péptidos/farmacología , Pseudomonas aeruginosa/metabolismo , Estabilidad ProteicaRESUMEN
Amyloid fibrils (AFs) are highly ordered nanofibers composed of proteins rich in ß-sheet structures. In this study, the impact of heating conditions relevant in food processing on AF formation of wheat gluten (WG) was investigated. Unheated and heated WG samples were treated with proteinase K and trypsin to solubilize the nonfibrillated protein, while protein fibrils were extracted with 0.05 M sodium phosphate buffer (pH 7.0) from the undissolved fraction obtained by the same enzymatic treatment. Conditions (i.e., heating at 78° for 22 h) resembling those in slow cooking induced the formation of straight fibrils (ca. 700 nm in length), whereas boiling WG for at least 15 min resulted in longer straight fibrils (ca. 1-2 µm in length). The latter showed the typical green birefringence of AFs when stained with Congo red. Their X-ray fiber diffraction patterns showed the typical reflection (4.7 Å) for inter-ß-strand spacing. These results combined with those of Fourier transform infrared and thioflavin T spectroscopy measurements validated the identification of ß-rich amyloid-like fibrils (ALFs) in dispersions of boiled WG. Boiling for at least 15 min converted approximately 0.1-0.5% of WG proteins into ALFs, suggesting that they can be present in heat-treated WG-containing food products and that food-relevant heating conditions have the potential to induce protein fibrillation.
RESUMEN
Plant natriuretic peptides (PNPs) are hormones that have been extracted from many different species, with the Arabidopsis thaliana PNP (AtPNP-A) being the most studied among them. AtPNP-A is a signaling molecule that consists of 130 residues and is secreted into the apoplast, under conditions of biotic or abiotic stress. AtPNP-A has distant sequence homology with human ANP, a protein that forms amyloid fibrils in vivo. In this work, we investigated the amyloidogenic properties of a 34-residue-long peptide, located within the AtPNP-A sequence, in three different pH conditions, using transmission electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy, Congo red and Thioflavin T staining assays. We also utilize bioinformatics tools to study its association with known plant amyloidogenic proteins and other A. thaliana proteins. Our results reveal a new case of a pH-dependent amyloid forming peptide in A. thaliana, with a potential functional role.
RESUMEN
Silkmoth chorion is a fibrous structure composed mainly of two major protein classes, families A and B. Both families of silkmoth chorion proteins present a highly conserved, in sequence and in length, central domain, consisting of Gly-rich tandem hexapeptide repetitive segments, flanked by two more variable N-terminal and C-terminal arms. Primary studies identified silkmoth chorion as a functional protective amyloid by unveiling the amyloidogenic properties of the central domain of both protein families. In this work, we attempt to detect the principal source of amyloidogenicity of the central domain by focusing on the role of the tandem hexapeptide sequence repeats. Concurrently, we discuss a possible mechanism for the self-assembly of class A protofilaments, suggesting that the aggregation-prone hexapeptide building blocks may fold into a triangle-shaped ß-helical structure.
Asunto(s)
Amiloide/química , Amiloide/metabolismo , Bombyx/metabolismo , Corion/química , Corion/metabolismo , Oligopéptidos/química , Oligopéptidos/metabolismo , Secuencias Repetidas en Tándem , Secuencia de Aminoácidos , Proteínas Amiloidogénicas/química , Proteínas Amiloidogénicas/metabolismo , Animales , Proteínas de Insectos/química , Proteínas de Insectos/metabolismo , Modelos Moleculares , Agregado de Proteínas , Agregación Patológica de Proteínas , Conformación Proteica , Análisis EspectralRESUMEN
Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow. In addition, the approach is effective against drug-resistant clinical isolates of Escherichia coli and Acinetobacter baumannii, reducing bacterial load in a murine bladder infection model. Our results indicate that redundant APRs are weak points of bacterial protein homeostasis and that targeting these may be an attractive antibacterial strategy.
Asunto(s)
Acinetobacter baumannii/metabolismo , Proteínas Bacterianas/química , Escherichia coli/metabolismo , Proteoma/química , Proteostasis , Acinetobacter baumannii/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Escherichia coli/genética , Agregado de Proteínas , Pliegue de Proteína , Proteoma/genética , Proteoma/metabolismoRESUMEN
Human zona pellucida (ZP) is composed of four glycoproteins, namely ZP1, ZP2, ZP3 and ZP4. ZP proteins form heterodimers, which are incorporated into filaments through a common bipartite polymerizing component, designated as the ZP domain. The latter is composed of two individually folded subdomains, named ZP-N and ZP-C. Here, we have synthesized six 'aggregation-prone' peptides, corresponding to a common interface of human ZP2, ZP3 and ZP4. Experimental results utilizing electron microscopy, X-ray diffraction, ATR FT-IR spectroscopy and polarizing microscopy indicate that these peptides self-assemble forming fibrils with distinct amyloid-like features. Finally, by performing detailed modeling and docking, we attempt to shed some light in the self-assembly mechanism of human ZP proteins.
Asunto(s)
Glicoproteínas/química , Agregado de Proteínas , Humanos , Simulación del Acoplamiento Molecular , Multimerización de Proteína , Estructura Cuaternaria de ProteínaRESUMEN
Apolipoprotein A-I (apoA-I) is the major component of high density lipoproteins and plays a vital role in reverse cholesterol transport. Lipid-free apoA-I is the main constituent of amyloid deposits found in atherosclerotic plaques, an acquired type of amyloidosis, whereas its N-terminal fragments have been associated with a hereditary form, known as familial apoA-I amyloidosis. Here, we identified and verified four "aggregation-prone" segments of apoA-I with amyloidogenic properties, utilizing electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy and polarized light microscopy. These segments may act as conformational switches, possibly controlling the transition of the α-helical apoA-I content into the "cross-ß" architecture of amyloid fibrils. A structural model illuminating the structure of amyloid fibrils formed by the N-terminal fragments of apoA-I is proposed, indicating that two of the identified chameleon segments may play a vital part in the formation of amyloid fibrils in familial apoA-I amyloidosis.
Asunto(s)
Amiloide/química , Apolipoproteína A-I/química , Péptidos/química , Agregado de Proteínas , Secuencia de Aminoácidos , Amiloidosis Familiar/metabolismo , Amiloidosis Familiar/patología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Péptidos/síntesis química , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , SolucionesRESUMEN
Isolated atrial amyloidosis (IAA) is a common localized form of amyloid deposition within the atria of the aging heart. The main constituents of amyloid fibrils are atrial natriuretic peptide (ANP) and the N-terminal part of its precursor form (NT-proANP). An 'aggregation-prone' heptapeptide ((114)KLRALLT(120)) was located within the NT-proANP sequence. This peptide self-assembles into amyloid-like fibrils in vitro, as electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy and Congo red staining studies reveal. Consequently, remedies/drugs designed to inhibit the aggregation tendency of this 'aggregation-prone' segment of NT-proANP may assist in prevention/treatment of IAA, congestive heart failure (CHF) or atrial fibrillation (AF).