Toll like receptors in Chronic Lymphocytic Leukaemia

Understanding single amino acid repeats in proteins

"Single amino acid and trinucleotide repeats: function, evolution and human disorders"

Abstract Amino acid repeats (AARs) are common features of protein sequences; they are segments of proteins made up of simple patterns of amino acids, often strings of a single amino acid. They have quite frequently been recognised to be common features of eukaryotic proteins, they have several functions and are involved in a number of human diseases; one of which is the inability to form amino acid repeats due to formation of precipitates/aggregates. Despite of their versatility the amino acid repeats are classified into categories depicted on their characteristics, so much that it would seem appropriate to have a database where all these can be stored in and later used for analysis All these diverse facets of amino acid repeats are explored in this review. Introduction An amino acid is a simple organic compound containing both a carboxyl (—COOH) and an amino (—NH2) group that combine to form proteins. Large proportion of cells, muscles and tissue in the human body are primarily made up of amino acids, the structure and function of these proteins are depended on where the amino acids are localised and how they are inter-connected to each other, being a total of twenty amino acids found within proteins expresses an immense range of chemical versatility. PhD student Luo and scientist Nijveen both wrote an article about understanding and identifying amino acid repeats (AARs); they suggested a majority of AARs are found in protein sequences since they have a specific role in protein function in eukaryotes in addition to this; Spanish researchers Subirana and Palau have written a hypothesis on the structural features of single amino acid repeats in proteins and had suggested while amino acids are able to form repeats some amino acids cannot, this may be due to the fact that those amino acids can form aggregates because of the formation of incipient lamellar crystals. Subirana and Palau mention in their abstract that single amino acid repeats found in different kind of proteins can be pathogenic, similarly Luo and Nijveen also mention the potential risks leading to disease due to abnormal functions caused by variations in sequence length, according to Luo and Nijveen; the variations to the length of the sequences and point mutation in repeat regions occur due to simple repeat patterns generated by DNA slippage, in addition; four Indian chemists; Katti, Sami-subbu, Ranjekar and Gupta studied the aspect of amino acid repeat patterns in protein sequences; their diversity and structural-functional implications and they point out that simple sequence repeats originate from replication errors and unequal crossing-over which are caused by the formation of slipped strands or hairpins; they further explain that these fall into the category under unusual DNA secondary structures, they continue to explain that

these repeats which are located in the coding region may be translated into single amino acid repeats which can then dictate protein structure and function. Subirana and Palau explain that in many cases the repeats give rise to aggregates which build abnormal actions in the cell, they continue by claiming that these actions are pathogenic but then later go on stating that this has been proved wrong because even in the absence of aggregates; toxic behaviour was still detected. According to Luo and Nijveen; inter-domain aggregation can be prevented by ‘gate-keeper’ residues which stabilise the leucine-rich repeat and WD repeat; they originate from internal gene duplication and are functional domain repeats that contain complex patterns, Katti et al refers to these patterns as periodic and mentions that there is one advantage of these patterns and that is that they compare and contrast similar functional groups which then create zip-like interactions with target molecules, they continue on by explaining that this provides a different perspective on predicting structural models and the design of new proteins. Luo and Nijveens’ article on Understanding and identifying amino acid repeats looks into the classification aspect of the AAR and the different categories they are allocated to depending on the characters of the repeat units, they also look into and quite briefly define the three major approaches for detecting amino acid repeats which are; the self-comparison strategy, the pattern recognition strategy and the complexity measurement strategy. The article starts off with brief background information about single amino acid repeats and ends with what they developed and what they hope their product will do to aid in the identification of different types of protein sequences. In Subirana and Palau’s’ article on Structural features of single amino acid repeats in proteins they mention in the first part of the article that they will throughout the paper clarify fibrillary aggregation of single amino acid repeats are related to the process of polymer crystallisation in lamellar crystal and they will also analyse why some single amino acid repeats are commonly found in nature. They start off their article briefly explaining what they will be mentioning throughout the paper and go on describing the role of amino acid repeats in proteins, they end their article mentioning both processes for protein folding; protein aggregation and homo- polymer crystallisation and that they should be considered as equal. Katti et al article on Amino acid repeat patterns in protein sequences: their diversity and structural- functional implications is all about creating a database that carries an infinite amount of information on proteins containing single amino acid repeats of various types and end their article reflecting what their study provides in the sense of protein sequences. Luo and Nijveen looked into classification of AAR patterns at sequence level; the writers introduce three approaches to classifying AARs into different categories depending upon; the characteristics. Sequence similarity, distance and the complexity of the sequence pattern of the repeat units, they then later mention that the approaches used to classify AARs being based on the protein sequence are

insufficient to reveal the biological significance of AARs because proteins play their functional roles by folding into particular secondary and tertiary structures, which are difficult to construe through amino acid patterns at sequence level. The writers gave an overall description of each approach; the first approach to classifying AARs was according to the similarity among the repeat units. AARs were classified into two main groups; perfect repeats and imperfect repeats or otherwise termed as divergent repeats. Perfect repeats had identical repeat units whereas imperfect/divergent repeats had the opposite; they were extremely variable but still recognisable. The second approach was based on the distance between each unit; they were classified as either tandem repeats (TRs) or non-tandem repeats (NTRs), units in TRs were continuously spread out whereas units in NTRs were scattered. The third approach was based on the complexity of the sequence pattern where the AARs can be classified as simple repeats which refer to continuous runs of amino acid residues or complex repeats which have sophisticated patterns of repeat units with variable lengths ranging from ten to a hundred residues. There are a few human disorders with regards to AARs; Luo and Nijveen mention amino acid repeats can sometimes cause mis-folding of prion proteins which are highly populated in the nervous system but also occurs in other tissues throughout the body, furthermore can modify the repeat length which may result in abnormal function, they further explain this by introducing a typical case known as the expansion of polyQ; this phenomenon results in many neurological disorders such as mental retardation, Huntington Disease and muscular dystrophy; this disease is involved in muscle weakness and loss of muscle tissue which deteriorates over time. Subirana and Palau explain that because expressed trinucleotide repeats (TNRs) at DNA level generate single amino acid repeats in silent regions of the genome, an abnormality in the DNA structure may cause inability of expansion of the trinucleotide repeats thus will be unable to produce single amino acid repeats in nature, they go on by explaining that this phenomenon will not only cause problems to the RNA structure level and effect the availability of tRNA but also may prevent transcription of DNA sequences to occur in the cell, according to Subirana and Palau; these expansions can quickly become associated with diseases when the TNRs expansion reaches a certain threshold due to alternative DNA structures. Subirana and Palau constructed a table (Table 1) in their article and interpret the data; their interpretation of the table was about how many single amino acid repeats will tend to crystallise as incipient lamellar structures and will therefore cause insoluble aggregates which will in turn lose the cells’ effectiveness. They carry on by explaining that the resistance to aggregation present is due to the amphipathic nature of the amino acid side chains; this means they have both polar and non-polar portions in its structure. Katti et al end their article by outlining their expectations from both their database and their overall study; they hope their database will reveal the extent of repeat

patterns and to aid in further analysis of internal repeats from their origin and knowing beforehand of any implications on protein structure and function that follow, they expect their study to be further extended using amino acid similarity mediums in addition to identity matches. Subirana and Palau end their article by giving an overview characterising single amino acid repeats and contrasting between polymer crystallisation and protein aggregation; they do this by stating the likelihood of long repeats of single amino acid being avoided in proteins so they can either aggregate the writers used hydrophobic amino acids as an example here, or it will have strong electrostatic interactions such like charged amino acids do which will then precipitate proteins with an opposite charge, and also mentioning how the length of the repeats will depend on the properties of each amino acid side chain. They end with pointing out that polymer crystallisation can be well predicted by simulation methods that have been developed for folding protein. They further explain that both protein aggregation and homo-polymer crystallisation should be considered as the same concept and should result in a cross-fertilisation of both fields. Luo and Nijveen conclude their article by introducing the database they produced and clarify that the data base will act as a powerful analysis tool for biologically interesting properties of any questions there may be. They also mention their future work where they will be making large-scale orthologous comparisons on protein repeats over a broad taxonomy range especially eukaryotes. Conclusion All three articles in their own ability have very well defined what amino acid repeats are, their role and what their implications may be. I was given the title “single amino acid repeats and trinucleotide repeats; function, evolution and human disorders”, but I decided to look into detail of only amino acid repeats that too specifically in proteins because what better location can amino acid repeats be present and also because I knew I would find a lot of articles which can relate to my topic. Each chosen article had their own central point even though they were about the same topic, one article was mainly about the basic information on amino acid repeats, another article was mainly about the information that is required to produce a database about amino acid repeats and protein sequences, and the third article was mainly about aggregation formed by amino acids and how they affect the structural features of AARs.

Bibliography

Faux, N. (2012) ‘Single Amino Acid and Trinucleotide Repeats’, Advances in Experimental Medicine and Biology. Springer, pp. 26–40. Katti, M., Sami-Subbu, Ranjekar, P. and Gupta, V. (2000) ‘Amino acid repeat patterns in protein sequences: Their diversity and structural-functional implications’, Protein Science, 9(6), pp. 1203–1209. Luo and Nijveen (2013) ‘Understanding and identifying amino acid repeats’, Briefings in Bioinformatics, 15(4), pp. 582–591. Subirana, J. and Palau, J. (1999) ‘Structural features of single amino acid repeats in proteins’, FEBS Letters, 448(1), pp. 1–3.