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Consequences of Amino Acid Substitutions on Protein FunctionBY: Deepak Vishwanathrao Pawar | Category: Genetics | Submitted: 2017-04-03 07:04:27
Article Summary: "Positioning and properties of amino acids are key in determining the function of a protein. Mutations cause change in amino acid sequence of a proteins resulting in altered/modified function..."
Consequences of Amino Acid Substitutions on Protein Function
Authors: Deepak V Pawar1, Mahesh Mahajan1, Rakesh Kumar Prajapat1, Kishor U Tribhuvan1
1ICAR-NRCPB, I.A.R.I, New Delhi-12
From the time when the first protein sequences and structures have been determined, it has been clear that the position and properties of amino acids are key in determining the biological function of proteins. For example, the first protein structure to be discovered, haemoglobin provided a molecular basis for understanding the basis of genetic disease sickle cell anaemia. A single nucleotide mutation leads to a substitution of glutamate with valine is the basis of disease. The substitution is results in lower solubility of haemoglobin and also causes the molecules to form long fibres within blood cells which leads to the unusual sickle-shaped cells. Haemoglobin is just one of many examples now known where single mutations can have radical consequences on protein structure, function and thereby protein associated phenotype. With the availability of thousands or even millions of DNA and protein sequences now we have knowledge of many mutations, either naturally occurring or artificially induced.
Protein Features Relevant to Amino Acid Behavior
The function of protein is determined by a number of general properties
Cells also contain numerous compartments, the organelles, which can also have slightly
different environments from each other. Proteins in the nucleus often interact with DNA, meaning they contain different preferences for amino acids on their surfaces (e.g. positive amino acids or those containing amides most suitable for interacting with the negatively charged sugar-phosphate backbone). Some organelles such as mitochondria or chloroplasts are quite similar to the cytosol, while others, such as lysosomes and Golgi bodies are more alike the extracellular environment. Therefore, it is important to consider the likely cellular location of any protein before considering the consequences of amino acid substitutions.
a protein belongs in will generally give insights into the possible function. The processes that give rise to homologous protein families are speciation or duplication. Proteins related by speciation only are referred to as orthologues, these proteins have the same function in different species. Whereas proteins related by duplications are referred to as paralogues. Sequential rounds of speciation and intra-genomic duplication can lead to confusing situations where it becomes difficult to say whether proteins are paralogous or orthologous in nature. To be maintained in a genome over time, paralogous proteins are likely to evolve different functions (or have a dominant negative phenotype and so resist decay by point mutation. Differences in function can range from subtle differences in substrate (e.g. malate versus lactate dehydrogenases), to only weak similarities in molecular function (e.g. hydrolases) to complete differences in cellular location and function (e.g. an intracellular signaling domain homologous to a secreted growth factor (Schoorlemmer and Goldfarb, 2001)). At the other extreme, the molecular function may be identical, but the cellular function may be altered, as in the case of enzymes with differing tissue specificities.
How mutations affect the protein function
Several studies have been carried out previously in an attempt to decipher general principles about the association between mutations and protein structure & function. SNPs are the point mutations which are present at a measurable frequency a population. They can occur either in coding or non-coding DNA. They may influence regulatory mechanisms such as promoter activity (gene expression), messenger RNA (mRNA) conformation (stability), and subcellular localization of mRNAs and/or proteins. Coding SNPs can be further being divided into two main categories, synonymous (where there is no change in the amino acid they code for), and non-synonymous. synonymous SNPs tend to occur much more frequently than Non-synonymous SNPs. The main reason for this is the natural selection force which keeps deleterious effect of Non-synonymous mutations in check. Site-directed mutagenesis is a powerful tool for discovering the importance of an amino acid in the function of the protein. Gross changes in amino acid type can reveal sites that are important in maintaining the structure of the protein. Peracchi (2001) has reviewed the use of site-directed mutagenesis to investigate mechanisms of enzyme catalysis.
Hanks SK, Quinn AM, Hunter T. (1988). The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science 241: 42-52.
Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massague J, et al. (1995). Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature 376: 313-320.
Parekh RB, Rohlff C. (1997). Post-translational modification of proteins and the discovery of new medicine. Curr Opin Biotechnol 8: 718-723.
Peracchi A. (2001). Enzyme catalysis: removing chemically 'essential' residues by sitedirected mutagenesis. Trends Biochem Sci 26: 497-503.
Schoorlemmer J, Goldfarb M. (2001). Fibroblast growth factor homologous factors are intracellular signaling proteins. Curr Biol 11 : 793-797.
About Author / Additional Info:
I am PhD research scholar, pursuing PhD at IARI, New Delhi in the discipline of Molecular Biology and Biotechnology. I am working on blast disease resistance in O. sativa
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