University Essay: How Amino Acid Sequences Influence Amyloid Formation

This essay delves into the factors that cause proteins with varying amino acid sequences to form amyloids, which are implicated in neurodegenerative disorders like Alzheimer's disease. It discusses how normal proteins lose their physiological properties and deposit as plaques, disrupting organ function. The essay highlights the role of amyloid beta peptides, steric zippers, and glutamine/asparagine-rich segments in amyloid formation and toxicity. It also addresses protein misfolding, environmental factors, and the transformation of amyloids into prions. The piece differentiates between beneficial and pathogenic amyloids, emphasizing the life-threatening potential of amyloidosis and the significance of understanding these processes. Desklib offers a range of resources, including past papers and solved assignments, to aid students in their studies.

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Title: What makes proteins with different amino acids sequences form amyloids?
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What makes proteins with different amino acids sequences form amyloids? 2
What makes proteins with different amino acids sequences form amyloids?
Most of the pathogenic amyloid proteins are formed when the normal healthy proteins lose their
natural physiological properties and get deposited around the cells in form of plaque basically
originating from plasma, harnessing the normal functioning of the organs and the tissues
(Reynaud, 2010). These amyloids have a significant contribution in development of
neurodegenerative disorders like Alzheimer’s disease, parkinson’s disease etc.
Histologically, the amyloids appear like fluffy and amorphous in H&E stains (Orvis, 2016). The
amyloidosis may originate by themselves (as primary amyloidosis) or may appear in
coordination to the other diseases (secondary amyloidosis). The amyloids are known to deposit at
the organs like kidneys, liver, tongue, skin, heart, brain and the peripheral nerves. The damage of
the organs due to amyloids is irreversible.
In case of Alzhiemer’s disease, the water soluble amyloid beta peptides (Ab) chains of approx.
39 to 43 amino acids assemble together and deposit over the neurons making them neurotoxic
(Matsuzaki, 2014). The amyloid beta peptides bind to a sugar lipid Monosialoganglioside GM1,
when it is present in clusters in presence of chloestrol and transforms into aalpha helix structure
from a random coil. The binding and coiling is mediated by the CH-TT interactions between
carbohydrate associated to GM1 proteins and the aromatic side chains of Ab. As the
concentration of Ab sheets increases above a threshold level and beyond, the aggregated beta
sheets are formed leading to secondary beta sheets and helical structure (Matsuzaki, 2014). As
the disease progresses further the ratio of Ab/GM1 elevates the aggregates increase in size and
become more cytotoxic.
It implies that when the amino acid sequences get favourable environment with cholesterol and
other constituents, they assemble together forming aggregates.
According to a research by Howard Hughes Medical Institute (2010), there are certain key
factors which make the proteins fibrous and sticky clumps which render the cellular activities to
slow down. The order of the amino acids is determined by the proteins and the genes. According
to a research by Eisenberg, the triplets of genetic codes give signal to start or stop the production

What makes proteins with different amino acids sequences form amyloids? 3
of proteins. The amyloids form a tight bond between them known as Steric zippers which makes
the protein strands, stack over each other forming fibres. These fibres have self binding capacity
to clog the organs and kill the cells (Howard Hughes Medical Institute, 2010).
The experiment showed that the enzyme ribonucleaseA when left under favourable conditions,
the protein segments formed self gluing amyloids. In the folded proteins, the position of high
propensity segments was not on the surface. The formation of amyloids is also triggered by the
changes in protein structure due to heat and chemicals through the process of denaturing
(Ahmed, 2013). These proteins have structural flexibility that leads to formation of amyloid
fibrils.
The amyloids can join together in many different arrangements of interconnecting proteins with
help of steric zippers. Different morphologies of the protein structures is defined by the different
types of variations in steric zippers (Howard Hughes Medical Institute, 2010). Eisenberg argued
that the different amino acids of same protein may form different steric zippers leading to
different stacking patterns (Howard Hughes Medical Institute, 2010). The toxicity of different
amyloid segments is dependent on the position of steric zipper on the fibril.
Sabate, Rousseau, Schymkowitz and Ventura (2015) discovered that the presence of large
segments of Glutamine/ Asparagine amino acids is found to be more toxic and disease causing in
nature. The amino acid composition of these regions is largely accountable for the toxic nature of
these amyloids rather than their sequence.
Basically the conformation changes in different polypeptides lead to self assembling tendency of
proteins which result into toxic amyloids (Rameau, 2016). The prion forming domains make
these amyloids infections and transmissive.
Two different types of Amyloid polypeptides occur. In the first category, the self assembly is
mediated by the short strands of high propensity whereas in second type, there are weaker
interactions between the polypeptide chains leading to disordered pattern ultimately results into
formation of amyloids (Just, 2012).

What makes proteins with different amino acids sequences form amyloids? 4
The protein folding is a complex process taking place in theEndoplsmic Reticulum which
requires iterative and coordinated interaction between different cellular proteins (Chitiand
Dobson, 2017). Correct folding of proteins is vital for the normal body functions and begins
when the polypeptide chain is stillunder synthesis. However the formation of amyloids is
regarded as Protein Misfolding (Blanko and Blanco, 2017). It leads to formation of intra and
extra cellular fibrous aggregates which have a damaging impact on the cells. The misfolding
conformations may cause different structural alterations making the strands infectious and
contributing to the pathology of many diseases (Sharma, 2013). The post translational
modifications which cause the formation of amyloids may include the covalent modifications,
development of Disulfide bonds between the Cysteines, and other similar changes in structure.
Conclusively, it is evident that the formation of amyloids takes place with the contribution of
different factors. The assembly of soluble proteins results into formation of insoluble and non
biodegradable fibrils (Jarosz, 2016). These fibrils or fibres give rise to several diseases occurring
due to structural changes in the proteins aggregates.
A number of environmental factors also increase the risk of amyloid formation and protein
misfolding such as exposure to the things which adversely influence the mitochondria and
elevate the oxidative damage to the proteins (Reynaud, 2010).
The amyloids may also give rise to self propagating structures known as prions. Many researches
regard this conversion of amyloids into prions as evolutionary mechanism (Zambrano et al,
2015). The amyloids involved in disease causing mechanism are capable to seed the formation of
soluble amyloids forms of proteins both in vitro and vivo.
A research by Roberts (2016) asserts that there are good and bad amyloids. The good amyloids
are necessary for the organism health, signaling, storage and scaffolding in different types of
organisms. The pathologically infectious amyloids known as prions are highly infectious and
transmissive through epigenetic inheritance and responsible for the occurrence of many
hazardous diseases (Roberts, 2016).

What makes proteins with different amino acids sequences form amyloids? 5
Good proteins may turn bad. The amyloidosis may be extremely life threatening (Mattson,
2003). For example, the malignant cells may give rise to aggregates of monoclonal
immunoglobulin light chains, as seen in case of Multiple Myelonema or ‘Mad Cow’ Disease.
The patient may perceive conduction abnormalities due to disruption of cardiac cells by the
amyloids resulting into stiff ventricles and severe diastolic dysfunction.

What makes proteins with different amino acids sequences form amyloids? 6
References
Ahmed,A.B. 2013. Breaking the amyloidogenicity code: Methods to predict amyloids from
amino acid sequence. FEBS Letters 587 (2013) 1089–1095. Available from:
https://cyberleninka.org/article/n/483161.pdf. [Accessed 25 Jan 2019].
Blanco A, and Blanco, G. 2017.Posttranslational Protein Modifications.Medical Biochemistry.
2017, pp. 535-545. Doi: https://doi.org/10.1016/B978-0-12-803550-4.00024-0
Chiti, F. and Dobson, C.M., 2017. Protein misfolding, amyloid formation, and human disease: a
summary of progress over the last decade. Annual review of biochemistry, 86, pp.27-68.
Jarosz, H., Noble,E and Rushworth,J. 2015. Amyloid-β Receptors: The Good, the Bad, and the
Prion Protein. February 12, 2016.The Journal of Biological Chemistry.291, 3174-
3183.doi: 10.1074/jbc.R115.702704
Just,W. 2012. Breaking the amyloidogenicity code: Methods to predict amyloids from amino
acid sequence. FEBS Letters; 8(587), 17 April 2013, pp. 1089-1095
Matsuzaki, K.2014. How do membranes initiate Alzheimer's Disease? Formation of toxic
amyloid fibrils by the amyloid β-protein on ganglioside clusters. AccChem Res. 2014 Aug 19;
47(8):2397-404. doi: 10.1021/ar500127z
Mattson,M.P., 2013. Good and Bad Amyloid Antibodies. Science. 26 Sep 2003: 301(5641), pp.
1847-1849. DOI: 10.1126/science.301.5641.1847
Orvis, A. 2016.AMYLOIDOSIS: When good proteins go bad. Available from:
https://slideplayer.com/slide/3498495/ [Accessed 25 Jan 2019].
Rameau, R.D.2016. The Human Disease-Associated Aβ Amyloid Core Sequence Forms Functional
Amyloids in a Fungal Adhesin. DOI: 10.1128/mBio.01815-15
Reynaud, E. (2010) Protein Misfolding and Degenerative Diseases. Nature Education 3(9):28
Roberts, R.G.,2016. Good Amyloid, Bad Amyloid—What’s the Difference? January 26, 2016
DOI: https://doi.org/10.1371/journal.pbio.1002362

What makes proteins with different amino acids sequences form amyloids? 7
Sabate, R., Rousseau, F.,Schymkowitz,J. and Ventura, S . 2015. What Makes a Protein Sequence
a Prion? January 8, 2015. DOI: https://doi.org/10.1371/journal.pcbi.1004013
Sharma,A. 2013. Protein Folding. Bioactive Food as Dietary Interventions for Liver and
Gastrointestinal Disease.2013, Pages 623-655
Zambrano, R., Conchillo-Sole, O., Iglesias, V., Illa, R., Rousseau, F., Schymkowitz, J., Sabate,
R., Daura, X., and Ventura, S. 2015.PrionW: a server to identify proteins containing
glutamine/asparagine rich prion-like domains and their amyloid cores. Nucleic acids
research, 43(W1), W331-7.