MadSci Network: Genetics

Re: what happens when protein changes & contains only 1479 amino acids

Date: Wed Oct 27 06:17:53 2004
Posted By: Joshua Chai, Student Doctor, School of Clinical Medicine, University of Cambridge, UK
Area of science: Genetics
ID: 1098431699.Ge

Hi Laura,

Cystic fibrosis is a good example of how a single amino acid change can 
lead to disastrous outcomes. Just to remind ourselves, cystic fibrosis is 
an autosomal recessive multisystem disease characterised by the 
production of abnormally thick mucus. Affected organs include the lung, 
the pancreas, the reproductive tract, etc. It has been estimated that 1 
in 25 Caucasians are heterozygous carriers of the defected CF gene.

The mutated gene is located on chromosome 7 and it encodes for the cystic 
fibrosis transmembrane regulator (CFTR) which is a modulator of a 
membrane chloride channel. As your have pointed out, the defect CFTR 
peptide is just 1 amino acid shorter than normal, then how does it lead 
to such profound effect? The reason can be understood if we re-visit some 
basic biochemical concepts. Peptide chains have 4 degrees of 

1. primary conformation concerns about the sequence of amino acid in the 
peptide chain; 
2. secondary conformation concerns about the hudrogen bonding that gives 
rise to basic structure like alpha-helices and beta-pleated sheets, etc.; 
3. tertiary conformation concerns about the actual folding of the protein 
into its functional shape; 
4. whereas quaternary conformation concerns about how individual folded 
protein are linked together in a functional unit (e.g. 4 folded globin 
chains linked as a single haemoglobin molecule). 

It turns out that the most important functional determinant of protein 
structure lies in its higher degree conformation i.e. tertiary and 
quaternary. This is to say that the most important functional feature of 
a protein is its 3-D shape. Individual amino acid can be changed, or even 
inserted/deleted, but as long as the crucial amino acids that hold the 
protein together and determine the folding of the peptide remained, the 
shape of the resulting protein would be the same, so as its function. 
However, in cystic fibrosis, the missing amino acid is in a crucial 
position that contribute to the structural folding of the resulting 
peptide. Therefore, the folding of the CFTR becomes defective, and a non-
functional CFTR is produced. AS a result, chloride ion transport is 
disrupted across the cell surface leading to the production of abnormally 
thick mucus. Perhaps an even more impressive example is sickle-cell 
anaemia. The genetic abnormality is a single nucleotide change in the DNA 
leading to an amino acid substitution in the gene coding for the beta-
globin chain (Glu -> Val at position 6). This single amino acid 
substitution (due to its crucial posision), with exactly the same 
resultant peptide length, is enough to disrupt the tertiary conformation 
of the beta-globin chain leading to all clinical manifestation of sickle-
cell anaemia.

Genetics is a fascinating subject and I hope the above information helps:-

Joshua Chai
Student DOctor
School of Clinical Medicine
University of Cambridge, UK

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