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Hereditary amyloidosis

Amyloid describes various types of protein aggregations that share specific traits when examined microscopically. The name amyloid comes from the early mistaken identification of the substance as starch (amylum in Latin), based on crude iodine-staining techniques. For a period the scientific community debated whether or not amyloid deposits were fatty deposits or carbohydrate deposits until it was finally resolved that it was neither, rather a deposition of proteinaceous mass. more...

Hairy cell leukemia
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Hereditary amyloidosis
Hereditary angioedema
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Specifically, amyloid deposits are extracellular, thioflavin s positive, and exhibit apple-green birefringence when stained with congo red. Other indicators exist, such as serum amyloid p-component binding. Since these are indirect indicators, biophysicists have redefined amyloid using a canonical set of biophysical characteristics (see below), and this seems to cause a low level of conflict between histologists and biophysicists.

The phenotypes of genetically transmitted amyloid diseases are often inherited in an autosomal dominant fashion. Sometimes, the difference between aggressive amyloid diseases and senescent amyloid diseases is due to a mutation which makes the protein more prone to aggregation. Most commonly seen are point mutations which affect the cohesiveness of the protein and promote misfolding; other mutations cause aggregation-prone pieces of the protein to be cleaved off from the rest of the protein.

Diseases featuring amyloid

It should be noted that in almost all of the organ-specific pathologies, there is significant debate as to whether the amyloid plaques are the causal agent of the disease or if they are instead a symptom downstream of a common ideopathic agent. The associated proteins are indicated in parentheses.

  • Systemic amyloidosis
    • Primary amyloidosis
      • Mutations in lysozyme, transthyretin, apolipoprotein B, fibrinogen
    • Secondary amyloidosis
      • AA amyloidosis (amyloid A protein, an acute phase protein due to chronic inflammation)
      • AL amyloidosis (immunoglobulin light chains)
      • Gelsolin amyloidosis (plasma gelsolin fragments).
    • Familial or Hereditary amyloidosis
      • Most commonly caused by mutations in the transthyretin protein, but in rare occurrences can also be caused by apolipoprotein A1, gelsolin, fibrinogen, and lysozyme mutations.
      • Primarily caused by genetics, believed to be autosomal dominant, high probability of passage to offspring
      • Appalachian type amyloidosis is perhaps the most well known type
  • Organ-specific amyloidosis
    • Diabetes mellitus type 2 (amylin, also known as IAPP)
    • Neurology
      • Alzheimer's disease (Aβ 39-42)
      • Parkinson's disease (alpha-synuclein) -- biophysical definition
      • Huntington's disease (huntingtin) -- biophysical definition
      • Spongiform encephalopathies
        • Creutzfeldt-Jakob disease (PrP in cerebrum)
        • Kuru (diffuse PrP deposits in brain)
        • Fatal Familial Insomnia (PrP in thalamus)
        • Bovine spongiform encephalopathy (PrP in cerebrum)
      • Congophilic angiopathy (Amyloid beta)
      • congestive heart failure; some instances (PrP in heart)
    • Inclusion body myositis
  • Iatrogenic conditions
    • insulin amyloidosis (injection-administered insulin)


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Simulations of human lysozyme: Probing the conformations triggering amyloidosis
From Biophysical Journal, 4/1/03 by Moraitakis, George

ABSTRACT A natural mutant of human lysozyme, D67H, causes hereditary systemic nonneuropathic amyloidosis, which can be fatal. In this disease, insoluble beta-stranded fibrils (amyloids) are found in tissues stemming from the aggregation of partially folded intermediates of the mutant. In this study, we specifically compare the conformation and properties of the structures adopted from the induced unfolding, at elevated temperature, using molecular dynamics, To increase the sampling of the unfolding conformational landscape, three 5 ns trajectories are performed for each of the wild-type and mutant D67H proteins resulting in a total of 30 ns simulation. Our results show that the mutant unfolds slightly faster than the wild-type with both wild-- type and mutant proteins losing most of their native secondary structure within the first 2 ns. They both develop random transient beta-strands across the whole polypeptide chain. Clustering analysis of all the conformations shows that a high population of the mutant protein conformations have a distorted beta-domain. This is consistent with experimental results suggesting that this region is pivotal in the formation of conformations prone to act as "seeds" for amyloid fiber formation.


Human lysozyme is a 130-residue protein found in secretions (e.g., saliva, sweat, and mucus) and more generally in leukocytes and kidneys. It is an enzyme that hydrolyzes preferentially the beta-1,4 glucosidic linkages between N-acetylmuramic acid and N-acetylglucosamine that occur in the mucopeptide cell wall structure of certain microorganisms (Chipman and Sharon, 1969). The wild-type human lysozyme has been crystallized and its structure elucidated by Artymiuk and Blake (1981) at 1.5 A resolution (Fig. 1, left). Its native structure consists of two domains: an alpha-domain that has four a-helices (A-D) and one 3^sub 10^ helix, and a beta-domain, which consists mainly of an antiparallel beta-sheet and a long loop. The active site is located in the cleft that is formed between these two domains. The protein contains four disulphide bonds of which two are located in the alpha-domain, one in the long loop of the beta-domain, and one that connects the two domains.

There are two known natural mutations of the human lysozyme: D67H and I56T (Pepys et al., 1993). They both cause autosomal dominant hereditary nonneuropathic systemic amyloidosis. This is a condition whereby there is tissue deposition in viscera and other body cavities of normally soluble autologous proteins as insoluble fibrils called amyloids. The core of these fibrils structure consists of beta-sheet with the strands perpendicular to the long axis of the fiber (Pepys, 1996). Amyloids can be formed from proteins of diverse sequence, fold, and function and are known to lead to serious medical conditions such as Alzheimer's disease and spongiform encephalopathies (Kelly, 1998). Although the mechanism of fibrilogenesis is not clear, it has been suggested that it is related to changes in stability and tendency to aggregate due to mutations. More specifically, Booth et al. (1997) proposed that a partially folded transient population of the amyloidogenic proteins, which lacks global cooperativity, undergoes structural transformation (a helix-- to-sheet transition) and creates the first template, the "seed", for further protein deposition and fibril formation. In a recent paper, Morozova-Roche et al. (2000) show that the presence of these "seeds" for both wild-type and the two natural mutants of human lysozyme facilitate the formation of fibrils.

We focus on the behavior of the D67H variant. The crystallized structure of this mutant (Booth et al., 1997) at 1.75 A resolution is quite similar to that of the wild-type (Fig. 1, right). However, because of the mutation, the network of hydrogen bonds that stabilizes the Bi-domain is destroyed. This results in a large concerted movement of the beta-sheet and the long loop within the beta-domain. This distortion of the beta-sheet propagates partially downstream to Ile56, the residue at the interface of the two domains, for which increased B-factors have been found.

To understand the behavior of the partially folded structures that may trigger amyloid formation, we explore the conformations adopted during the induced unfolding of the wild-type and mutants at high temperatures (500 K) using molecular dynamics (MD) simulations. The temperature denaturation of proteins using MD is considered as one of the most straightforward computational experiments (Brooks, 1998). The great advantigation of unfolding simulations is that they allow the investigation of the conformational properties at every point along the unfolding pathway (Li and Daggett, 1994). There are many examples of their use (Daggett, 2000) and these have led to detailed insight of experimental results of protein unfolding (Li and Daggett, 1998; Alonso and Daggett, 2000) and the study of the folding pathway (Karplus and Sali, 1995). Lysozyme from hen egg white has been extensively investigated by means of unfolding simulations (Mark and van Gunsteren, 1992; Hulnenberger et al., 1995; Williams et al., 1997; Kazmirski and Daggett, 1998; Gilquin et al., 2000) with the aim to investigate several issues such as the stability and folding of the protein. The human and hen forms of lysozyme have 60% sequence similarity but very similar 3D structure.

In our study, we attempt to examine and compare the structure and properties of the partially folded intermediates obtained from the induced unfolding of the wild-type and the D67H form.


The crystal structures of the wild-type (IREX) and the mutant (1LYY) lysozyme are the starting point of the simulations. Hydrogen atoms are added and the final system includes solvent molecules that are represented by the SPC216 model (Berendsen et al., 1981). All atoms are explicitly represented. The solvated model is contained in a rectangular box (70 X 70 X 70 A) using periodic boundaries conditions (Allen and Tildesley, 1987). The building of the protein models and all their simulations are carried out with the GROMACS suite of programs (Berendsen et al., 1995). The GROMOS 96 force field is used to describe the atomic interactions (van Gunsteren et al., 1996). For the correct treatment of long-range electrostatics, we make use of the particle mesh Ewald summation algorithm (Darden et al., 1993). The high frequency degrees of freedom from the covalent bonds of hydrogen atoms are constrained using the LINCS algorithm (Hess et al., 1997) and thus the time step is increased from 1 to 2 fs. The system is coupled to an external temperature bath with a separate bath for the solvent and the solute (Berendsen et al., 1984). The regulation of the pressure is achieved by means of a pressure bath. Data on the trajectories are saved every 0.2 ps. For these simulations, we use an in-house multiprocessor Origin 2000 with four CPUs. The total central processing unit time for all simulations was ~48 days.

To minimize the initial system, we use a combination of the conjugate gradients and steepest descent methods in which after every 50 steps of conjugate gradients, one step of steepest descent is performed. The minimization is terminated when the overall force of the system is 100 N or after 5000 steps. This protocol is first used to minimize hydrogen atom and water molecules positions and then extended to the whole system. To further optimize the arrangement of the solvent around the protein and alleviate high energy regions (hot spots), the water molecules only are assigned initial velocities from a Gaussian distribution generated from a random seed and then warmed up from 50 K to 300 K over 10 ps of MD. This is followed by equilibration of the water molecules at 300 K for 30 ps. Then the whole system (including the previously constrained protein) is assigned initial velocities from a Gaussian distribution generated by a random seed for 50 K, warmed up to 300 K for 10 ps, and finally equilibrated at this temperature for 1000 ps. The 1000 ps trajectory at 300 K serves as a control simulation. The last conformation of the system obtained from this trajectory is used as the starting structure for the unfolding simulation in which the system is warmed up to 500 K for 10 ps and is subsequently maintained at this temperature. To enhance the sampling of the unfolding pathway, long multiple trajectories are performed by assigning velocities generated from different seed numbers. Three 5000 ps high temperature (500 K) and three 1080 ps control (300 K) simulations are performed for each lysozyme form.

We thank the Biotechnology and Biological Sciences Research Council for computer hardware and the Engineering and Physical Sciences Research Council for a studentship to G.M.

This work has been carried out within the Biotechnology and Biological Sciences Research Council-sponsored Bloomsbury Centre for Structural Biology.


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George Moraitakis and Julia M. Goodfellow

School of Crystallography, Birkbeck College, University of London, London WC1E 7HX, United Kingdom

Submitted March 18, 2002, and accepted for publication September 18, 2002.

Address reprint requests to Julia M. Goodfellow, School of Crystallography, Birkbeck College, University of London, Malet Street, London WCIE 7HX, UK. Tel.: 44-01793-413208; E-mail:

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