Modeling Plasma Membranes and Proteins that Transport Small Molecules and Membrane Components
Author(s)
Klauda, Jeffery B.
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Abstract
Lipid membranes protect cells from unwanted compounds and proteins control the transport of substrates
between and across cellular membranes. The composition of these membranes varies significantly between
organisms and organelles within an organism, which ultimately plays an important role in membrane structure
and interaction with membrane-associated proteins. Our studies on the cytoplasmic membrane of E. coli with
its unique lipid containing a cyclopropane moiety on its chain demonstrate the importance of lipid diversity to
membrane structure and rigidity. Our E. coli membrane model agrees with known hydrophobic thicknesses of
transmembrane proteins and is thinner than existing simple models for the cytoplasmic membrane. With
accurate model membranes, simulations on membrane-associated proteins can provide insight on how
proteins transport substrate across the membrane or between membranes. Lactose permease (LacY) of E. coli
is a model for secondary active transporters (SATs) but most SATs have crystal structures in a single state in
the transport cycle. To study substrate transport mechanism, we have developed a simulation technique to
enhance conformational sampling of SAT proteins. This method was successful in obtaining the unknown
periplasmic-open state of LacY and our simulations agree with a multitude of experimental measurements
(FRET, DEER, accessibility studies, etc.). With a crystal structure in a single conformational state, our
method can probe other states in the substrate transport cycle. While SAT proteins span the lipid bilayer,
peripheral membrane proteins transiently bind to membranes and are involved in membrane signaling and
transport. Our multiple ms all-atom simulations of the peripheral membrane protein of yeast (Osh4) have
clarified how this protein binds to membranes. Previous experimental mutation studies suggested that Osh4
contained 2-3 distinct membrane binding domains. However, our simulations on similar model membranes
used in experiments demonstrate a single membrane binding region. Since the membrane binding region on
Osh4 agrees with previous experiments, it appears that Osh4 has a single large membrane binding domain.
Ultimately, our goal is to probe how Osh4 transports sterols and an important signaling lipid between
organelles in yeast.
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Date
2013-03-13
Extent
54:01 minutes
Resource Type
Moving Image
Resource Subtype
Lecture