Jasmonate Perception
Ning Zheng group (University of Washington) and collaborators
Although historically within the realm of kinase inhibitors
and ATP analogs, the field of small molecule therapeutics is broadening its
horizons towards under-targeted regulatory pathways. The ubiquitin ligase
system offers a most attractive pathway for specifically treating diseases
such as cancer and neurodegenerative disorders. The ubiquitin system utilizes
an enzymatic cascade that specifically tags protein targets with one or many
small ubiquitin proteins, generally signaling the cell to send that protein
for destruction. Many common chronic diseases involve critical deregulations
of this system, including the loss of destruction of β-catenin by the
ubiquitin ligase β-TrCP, a foundational mutation that underlies the
deadly progression of many colon cancers. In recent work by the Zheng group
and collaborators, Mother Nature provides a general lesson from plants
regarding ubiquitin ligase regulation by small molecule hormones. The
researchers recently discovered that the small-molecule hormones that
regulate plant physiology, including jasmonate, auxin, and gibberellins, work
on the molecular level by changing the function of ubiquitin ligases;
pursuant study of a complex provided insight into the mechanistic and
structural underpinnings of this phenomenon. Beamtime at GM/CA facilities was
critical for the researchers to solve a high-resolution structure detailing
the specific molecular bonds between the small molecule and its ubiquitin
ligase target. They found that the small defense hormone, jasmonate, sits in
a pocket, nestled between the ubiquitin ligase COI1 and its substrate, a JAZ
transcriptional repressor. The structure and subsequent biochemistry revealed
that the hormone sits perfectly between the two proteins and acts as
“molecular glue”, increasing the affinity of one protein for the
other. Interestingly, the complex of ubiquitin ligase, protein substrate, and
hormone can form only when all three members are present — if one is not
present, none of the members will associate with another. This molecular
insight into the inner workings of plant biology provides a fantastic model
for future development of drugs targeting the ubiquitin ligase system in
other biological systems.
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Figure: Tripartite complex: COI1
portion of ubiquitin ligase shown in green mesh, jasmonate shown in yellow
and red, and JAZ transcriptional repressor shown in orange. |
Citation: Sheard LB, Tan X, Mao H, Withers J, Ben-Nissan G,
Hinds TR, Kobayashi Y, Shu F-F, Sharon M, Browse J, He SY, Rizo J, Howe GA,
Zheng N. Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ
co-receptor. Nature. 2010 Nov 18; 468: 400-405. doi:
10.1038/nature09430.
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