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Compositions and Methods
for Regulating Intramembrane Proteases
Intramembrane
proteolysis is a widely conserved regulatory mechanism in species ranging from
bacteria to humans. The first description of intramembrane proteolysis came
from the investigation of cholesterol homeostasis, where the ER membrane-bound
transcriptional factor SREBP must be cleaved by an integral-membrane protease,
known as site-2 protease (S2P). This cleavage results in the release of the N-terminal
domain of SREBP, which contains a DNA-binding domain and a
transactivation domain. The N-terminal domain of SREBP regulates transcription
of a number of genes that collectively control biosynthesis of cholesterol and
fatty acid. Another prominent example of intramembrane proteolysis is the
proteolytic processing of the amyloid precursor protein (APP) by the
intramembrane protease g-secretase, which is central to the
development of Alzheimer’s disease. The cleavage
product of APP, amyloid b-peptide, exhibits pronounced toxicity to
neuronal cells and is thought to contribute to Alzheimer’s disease. More
recently, study of epidermal growth factor receptor (EGFR) signaling in Drosophila identified rhomboid as an
essential component in the signal-sending cells. Rhomboid, a putative
intramembrane protease, cleaves the ligand Spitz, which is inactive in its
full-length form, thus regulating EGFR signaling spatially and temporally.
There are four
families of integral membrane proteins that are though to catalyze intramembrane
proteolysis: the serine protease rhomboid, metalloprotease S2P, aspartyl
proteases presenilin (catalytic subunit of g-secretase) and
signal-peptide peptidase. The putative catalytic residues are predicted to be
below the membrane surface and within the hydrophobic core of the proteases. In
this case, since scission of peptide bonds requires the presence of water
molecules, how do hydrophilic water molecules enter the active site? More
importantly, if the active site is within the hydrophobic core of the
proteases, how do the substrate proteins gain excess to the catalytic residues?
Furthermore, are there some common principles that govern all four families of
intramembrane proteases? These fundamental questions need to be addressed by a
series of structures of the proteases at different stages of their action.
Researchers at
This invention elucidates
the method in which the movement of TMH5 of a rhomboid
intramembrane protease or the corresponding transmembrane helix in other
families of intramembrane proteases is restrained by compounds and inhibitors.
The restrained movement of TMH will result in a reduction of the intramembrane
protease activity of intramembrane proteases. Reduced protease activity of
intramembrane proteases provides a therapeutic treatment for diseases in which
intramembrane proteases play a contributing role. Such diseases could include neurological
disorders, cardiovascular diseases, cancer, and others.
Publications:
Wu, Z., Yan, W., Feng, L., Oberstein, A., Yan,
H.,Baker, R., Gu, L., Jeffrey, P.,Urban, S., Shi, Y., Structural Analysis of
a Rhomboid Family Intramembrane Protease Reveals a Gating Mechanisms for
Substrate Entry, Nature, Strucutral Biology, Vol. 13, #12, December 2006.
Baker,R.P>, Young,K., Feng,L., Shi,Y.,
Urban,S., Enzymatic Analysis of a Rhomboid Intramembrane Protease Implicates
Transmembrane Helix 5 as the Lateral Substrate Gate, PNAS USA, 2007, May
15:104(20) 8257-62.
For more information on
Laurie Tzodikov
Office of Technology
Licensing and Intellectual Property
4
New South Building
(609)
258-7256
(609)
258-1159 fax
tzodikov@princeton.edu