Structural and Evolutionary Insights Point to Allosteric
Regulation of TRP Ion Channels
Version 2 2019-05-31, 14:41
Version 1 2019-05-31, 14:35
Posted on 2019-05-31 - 14:41
ConspectusThe familiar pungent taste of spicy food, the
refreshing taste
of mint, and many other physiological phenomena are mediated by transient
receptor potential (TRP) ion channels. TRP channels are a superfamily
of ion channels that are sensitive to diverse chemical and physical
stimuli and play diverse roles in biology. In addition to chemical
regulation, some family members also sense common physical stimuli,
such as temperature or pressure. Since their discovery and cloning
in the 1990s and 2000s, understanding the molecular mechanisms governing
TRP channel function and polymodal regulation has been a consistent
but challenging goal. Until recently, a general lack of high-resolution
TRP channel structures had significantly limited a molecular understanding
of their function.In the past few years, a flood of TRP channel
structures have been
released, made possible primarily by advances in cryo-electron microscopy
(cryo-EM). The boon of many structures has unleashed unparalleled
insight into TRP channel architecture. Substantive comparative studies
between TRP structures provide snapshots of distinct states such as
ligand-free, stabilized by chemical agonists, or antagonists, partially
illuminating how a given channel opens and closes. However, the now
∼75 TRP channel structures have ushered in surprising outcomes,
including a lack of an apparent general mechanism underlying channel
opening and closing among family members. Similarly, the structures
reveal a surprising diversity in which chemical ligands bind TRP channels.Several TRP channels are activated by temperature changes in addition
to ligand binding. Unraveling mechanisms of thermosensation has proven
an elusive challenge to the field. Although some studies point to
thermosensitive domains in the transmembrane region of the channels,
results have sometimes been contradictory and difficult to interpret;
in some cases, a domain that proves essential for thermal sensitivity
in one context can be entirely removed from the channel without affecting
thermosensation in another context. These results are not amenable
to simple interpretations and point to allosteric networks of regulation
within the channel structure.TRP channels have evolved to be
fine-tuned for the needs of a species
in its environmental niche, a fact that has been both a benefit and
burden in unlocking their molecular features. Functional evolutionary
divergence has presented challenges for studying TRP channels, as
orthologs from different species
can give conflicting experimental results. However, this diversity
can also be examined comparatively to decipher the basis for functional
differences. As with structural biology, untangling the similarities
and differences resulting from evolutionary pressure between species
has been a rich source of data guiding the field. This Account will
contextualize the existing biochemical and functional data with an
eye to evolutionary data and couple these insights with emerging structural
biology to better understand the molecular mechanisms behind chemical
and physical regulation of TRP channels.
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Hilton, Jacob
K.; Kim, Minjoo; D. Van Horn, Wade (2019). Structural and Evolutionary Insights Point to Allosteric
Regulation of TRP Ion Channels. ACS Publications. Collection. https://doi.org/10.1021/acs.accounts.9b00075
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AUTHORS (3)
JH
Jacob
K. Hilton
MK
Minjoo Kim
WD
Wade D. Van Horn