Our research
interests
The majority of our work is focussed on ABC transporters - eukaryotic
ones at that, although we have significant experience in prokaryotic ABC
proteins, and plant major facilitator transporters as well.
If you are interested in what we do then read on, and if you are still
interested afterwards and want to know more then let me know!
Introduction
ATP binding cassette (ABC)
proteins are found in all 3 domains of life (prokaryotes and archaea
–“bugs”, and eukaryotes like you and I). They are responsible for an
abundance of transport roles whereby they “move” a substance across the
membrane of the cell so that it can be used (“import”) or so that it can be
excreted from the cell (“export”). A number of strange ABC proteins exist
that do not transport anything – in fact they appear to be involved in
other cellular process such as translational regulation and DNA repair.
However, the vast majority of ABC proteins are pumps, and in eukaryotes
most – if not all - are exporters, whilst prokaryotes mix it up with both
exporters and importers.
ABC transporters
in health and disease
Eukaryotic ABC proteins have
been grouped into 7 subfamilies based on the organisation of their 4
essential domains (2 ATP hydrolysing domains known as NBDs, and 2
substrate-transporting domains known as TMDs), as well as features such as
sequence homology and gene structure. These 7 families are known as…wait
for it… ABCA to ABCG (amazingly original nomenclature) . In
humans, there are 48 proteins across these 7 families and for pretty much
all the ones we have studied in detail there is a disease to go with the
normal physiological role. For example, ABCA4 is a protein involved in
retinal transport in rod and cone cells and defects in this transporter
underlie various degenerative visual disorders including Stargardt disease. Similarly, CFTR (ABCC7) is an ABC
transporter whose mis-function (or mis-expression) causes the western world’s most common
serious genetic disorder (cystic fibrosis).
ABC transporters
and multidrug efflux
At least three human ABC
transporters, namely P-glycoprotein (P-gp;
ABCB1), multidrug resistance associated protein 1(MRP1; ABCC1) and breast
cancer resistance protein (BCRP; ABCG2), have been shown to efflux the
Sigma catalogue, at least in vitro. How significant these pumps are in
tumour multidrug resistance is still debated but they are major players in
the ADMETox profile of pharmaceutical agents.
Our current
research
For the last few years most of
our ABC transporter research has been focussed on ABCG2. In collaboration with
the Callaghan lab and others we continue to work on ABCB1 and ABCA4, and
with Freddie Theodoulou we work on ABCD transporters. But ABCG2 is our
lab’s protein (I don't mean we own it of course), and we have been working
to understand its interactions with substrates, inhibitors and itself (the
protein forms dimers and higher order assemblies).
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