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The search for the interactome of the membrane protein VDAC: from epitopes to mitochondrial physiology

woensdag, 5 juli, 2006 - 17:00
Campus: Brussels Humanities, Sciences & Engineering campus
Faculteit: Medicine and Pharmacy
auditorium P. Brouwer
Inge Roman
doctoraatsverdediging

Mitochondria are the energy generating organelles
of the eukaryotic cell. They are delimited by 2
membranes. Their outer membrane contain very
large channels through which metabolites can pass
in and out in a controlled way. These channels – the
Voltage Dependent Anion Channel or VDAC – play
also important roles in programmed cell death,
steroidogenesis and can function as anchoring
points to the mitochondria.

Already numerous proteins are reported to interact
with VDAC but often these studies were indirect
and/or showed contradictive result. In this work a
more systematic approach was used to define the
largest set of potential VDAC interacting proteins,
this is the VDAC interactome.

A novel methodology was developed. It involved
screening an expression library of cellular proteins
for interaction with the membrane protein in its
native form. A key aspect of this method is based
on non-steady state kinetics. This methodology is
generally applicable for any protein and could thus
be used by other research groups and
pharmaceutical companies.

With this methodology a large set of putative VDAC
interacting partners was found. One of these
proteins was cytochrome c oxidase, an enzyme of
the respiratory chain complex, located in the inner
membrane of the mitochondria. The binding
between this protein and VDAC was never
reported before and further analyses revealed that
the interaction was also functional. Altogether
these results support a novel contact site between
the two mitochondrial membranes.

From all the remaining identified proteins the exact
sequence of the epitopes – the portion actually
interacting with the VDAC target – could be
obtained. This is important information for drug
design and could lead to more specific
pharmaceuticals and therapies. This work also will
contribute to the further understanding of
mitochondrial physiology.