Since the discovery in 2007 that a component of human semen called SEVI boosts
infectivity of the virus that causes AIDS, researchers have been trying to learn
more about SEVI and how it works, in hopes of thwarting its infection-promoting
activity.
Now, scientists at the University
of Michigan have determined the atomic-level, three-dimensional structure
of a SEVI precursor known as PAP248-286 and discovered how it damages cell membranes
to make them more vulnerable to infection with HIV. The work is described in
two new papers. The most recent, describing the structure, was published online
Nov. 17 in the Journal of the American Chemical Society. The paper describing
how PAP248-286 interacts with cell membranes appeared in the Nov. 4 issue of
Biophysical Journal.
PAP248-286 is a peptide---a chain of amino acids not long enough to be considered
a protein. Individual PAP248-286 peptides have a tendency to clump together
to form amyloid fibers called SEVI (semen enhancer of viral infection). Amyloid
fibers are of great interest because they are the calling cards of many neurodegenerative
diseases, such as Alzheimer's and Parkinson's, and aging-related diseases like
type-2 diabetes. Using NMR (nuclear magnetic resonance) spectroscopy, a technique
that not only yields atomic-level details of a molecule's structure, but also
shows how the molecule nestles into the membrane with which it interacts, researcher
Ayyalusamy Ramamoorthy and coworkers found that the structure of PAP248-286
is unlike that of most other amyloid-forming peptides and proteins.
In solution, SEVI is completely unstructured or has no definite shape and is
therefore ineffective. On the other hand, "when bound to the membrane,
it's in a spaghetti-like arrangement---a disorganized, loose coil," said
Ramamoorthy, a professor of chemistry and of biophysics. In contrast, most other
amyloid proteins assume a more ordered, helical configuration. Also unlike other
amyloid peptides, SEVI does not penetrate deep into the greasy region of the
cell membrane, but is located near the surface. Ramamoorthy and coauthors believe
the spread-out, disordered configuration and its location in the cell membrane
may explain the ability of SEVI fibers to enhance HIV infection, as the arrangement
provides more surface area with which the virus can interact.
A key finding of the second study is that PAP248-286 "shocks" the
membrane, inducing a structural change---a kind of dimple that allows HIV to
attach to and enter the cell.
Next, Ramamoorthy and colleagues hope to discern more structural details of
PAP248-286 and SEVI. They also plan to screen antioxidant compounds such as
green tea extract, curcumin and resveratrol (found in red wine) to see if such
compounds are capable of blocking SEVI's HIV-enhancing activity.
Posted November 19th, 2009
