Living life on the molecular scale, and other random musings from the paradigm of one in seven billion.
Tuesday, January 16, 2018
Tour your code: A is for….ATP7B: "The Copper Trader"
Happy New Year! And with the new year, I'm undertaking a new endeavour on my blog. In 2018, I'm
going to be taking a tour of genes found in the human genome. There are an
estimated 20,000 genes in our genetic code, so I may have to be somewhat curated list. I'm going to focus on genes that aren't as commonly known in the wide
world or covered by the media but have interesting functions or links to disease of interesting history. I'll be staying away from the 'famous' list because let's face it - there's already plenty of information and blog
posts regarding genes like BRCA. It also happens there's at least one gene for
every letter of the alphabet. So it's not hard to make the tour 26 stops from A-Z.
researching the ABCs of human genes and quickly came to the realisation that
gene names are well...pretty dry and terrible. Yet the genes themselves and
what they produce is endlessly fascinating. So don't be perturbed by the coded
names and dry nomenclature. Your genetic code is quite amazing, there just
needed to be a way to identify them in a universal way, and like most standardised things practicality is more important than fun flourishes.
Human genes are
actually named according to a convention set down by the HUGO Gene Nomenclature Committee (HGNC). This name
and symbol means there's a standard for official gene identification in
research and clinical practice, though it's also common for some genes to have
'common' names that are used in discussion in the scientific community. Genes
can also be named according to their position on their respective chromosome or
through standardised catalogue numbers in the various databases scientists use.
a standard for human genes, there is also some gold out there in terms of gene
names in other species - Sonic The Hedgehog, Tinman, INDY (I'm Not Dead Yet)
are all gene names, and are all genes from the Drosophila fly. Drosophila Melanogaster is a model organism
and is one of the most studied organisms. The annoying fruit flyactually plays a huge role in scientific
research! And it turns out when given the opportunity, scientists will seize it. But I digress....
This week: ATP7B
Common Name:Wilson Disease Protein (WND)
Expressed in the liver and
in small amounts in the brain
80 000 bases of DNA
sequence in total - only 7500 bases make up the protein sequence
Gene is located on
Physical Location is
Consists of 13 exons
(protein coding genetic segments)
Consists of 1465 amino
acids (protein building blocks, each encoded by 3 DNA bases)
Copper-Transporting ATPase 2
Protein is 165 kDa in size
Functions: adds copper
groups to new proteins; exports copper out of liver cells into bile
Disease: mutations in the
gene results in defective ATP7B causing Wilson's Disease
ATP7B is a gene
that encodesa proteincalled Copper-Transporting ATPase 2. This is
as a P-type ATPase. This group of proteins transport metals.
"I whip my domain back and forth". Copper-Transporting ATPase 2. Source: Wikipedia (CC).
Every cell in the human body, except red blood cells has a duplicated copy of the genome, but only certain
genes will be activated and making proteins in certain cells. This is how
humans have different organs and cell types - the genes being 'expressed' and
making proteins in liver cells (hepatocytes) will be different to those making
proteins in brain cells (neurons).
of 'domains'. These domains are what allow proteins to do their work. Usually
these domains give certain properties to a protein enabling them to interact
with other proteins, move through certain places, and drive reactions needed in the
cell. Proteins may can have multiple domains, with numbers depending on the function. The protein of ATP7B has
8 different domains - to bind its target, interact with targets and also for energy. It's a busy protein!
ATPases like Copper-Transporting ATPase 2 are a
class of protein that can take ATP (adenylpyrophosphatase)
and utilise it as a source of energy. ATP is the energy molecule of a cell. A
protein that can do this is able to use ATP to drive a reaction. The P -type indicates that ATP7B is able to
use phosphorylation to drive their action. ATPases are known as 'pumps' because
they act as transporters and bind and move something throughout the cell. Often
this action is across the cell wall. These types of pumps are found everywhere
in the body and serve many important functions from nutrient uptake in the
intestine,controlling nervous impulses
to secretion in the kidneys.
ATPase 2 has a domain that binds to copper. Copper-transporting
ATPase 2 is also able to bind zinc, cadmium, gold and mercury but has the
greatest affinity for copper.
Copper and other
'heavy metals' are needed in very tiny amounts in our cells for proper
function. If they build up they become toxic and can damage cells, and left untreated this can
result in death. Heavy metals can accumulate to
toxic levels not only due to fault in the cell that means there are not removed but also due to too much exposure.Each metal, like any element or chemical can be tolerated in different
amounts, and the excess will impact on different organs in different ways. Too much copper results in damage to the mitochondria of the cell (aka. the power house of the cell that produces all the ATP), and as a result the cell dies.
ATPase 2 is mostly found in an area of the cell called the Golgi Aparatus. At
the Golgi, proteins being made undergo their final modifications so they are
ready to undertake their function. It's the finish and polish station of the cell! Copper-transporting
ATPase 2 adds copper groups to proteins that require it. If copper levels start
exceeding normal levles, Copper-Transporting ATPase 2 will leave the Golgi and
will act to transfer copper out of the cell through the vesicles. This copper then
ends up in bile and is excreted. This protein is key in avoiding toxic buildup
of copper in cells.
A defect in the
sequence of ATP7B can result in Wilson's disease - that is, copper accumulation
due to a genetic disorder. There are over 300 mutations known to occur in the gene however only a small number result in Wilson's disease. Some mutations in the genetic code of ATP7B can mean the protein produced doesn't function correctly. These mutations can be changes to single DNA bases,deletions or frameshifts to the 3 base pair amino acid codes tat result in a different amino acid.The mutations are inherited in an autosomal
recessive way - the condition is found on the autosomes (non-sex chromosomes) and
requires 2 copies of the defect to result in the disease. Note: copper
accumulation and toxicity can occur for other reasons, Wilson's disease is
specifically due to the mutations in the genetic code!
is characterized by a number of symptoms that arise due to copper accumulation
and the symptoms usually occur in the nervous system and liver. This includes
vomiting, jaundice (yellowing skin and eyes), hallucinations ad muscle
stiffness. A really striking feature and symptom of copper accumulation is the
formation of Kayser-Fleischer rings on the eyes - see the picture below.
Kayser-Fleischer Ring on the eye (shown by arrow). Source: Wikipedia (CC)
To confirm Wilson's disease it must be determined whether it's a problem with ATP7B rather than another way that copper is accumulating. Diagnosis is
through appearance of symptoms associated with copper accumulation,liver
function tests, testing of serum and urine copper levels, MRI of the brain and
genetic testing of ATP7B. A further test can be done for levels of ceruloplasmin, an
enzyme that carries copper in the bloodstream. There actually isn't a
definitive test for Wilson's disease itself, but rather a combination oftests, and the gold standard - a liver biopsy
can determine if Wilson's disease is the cause of the symptoms and the copper
accumulation. Wilson's disease is not common - it occurs in approximately
1/30,000 people. Male and females are equally affected and it may occur
anywhere between 5 and 35 years of age.
And if you are
wondering, there is an ATP7A gene - it's produces a related, somewhat similar
protein (57% homologous) that transports copper across the cell membrane to
outside of the cell. Interestingly it's expressed everywhere in the body EXCEPT
the liver. It's found on the X chromosome, so is in a completely different
location and is sex-linked.
So there you have
it - our first stop on a tour of your genetic code - ATP7B.