Structural basis for biological force sensations
EMSL Project ID
50651
Abstract
The goal of this proposal is to understand how cells sense and respond to physical stimuli. The ability to detect physical forces underlies classic mechanosensations like hearing and less conspicuous processes including osmoregulation. We propose using cryo-EM to determine the structural and mechanistic basis of cellular volume regulation and auditory sound amplification. This work will provide long sought-after molecular insight into fundamental and medically relevant sensory systems.Aim 1: Determine the structural basis for the function of volume-regulated anion channels (VRACs).
Hypotonic swelling of vertebrate cells activates ubiquitously expressed VRACs formed by LRRC8 proteins. We aim to determine structures of homo- and hetero-meric LRRC8s in different functional states to understand the mechanism of stimulus sensing, gating, and ionic selectivity in this channel family.
Aim 2: Determine the structural basis for the function of potassium-chloride cotransporters (KCCs).
Swelling vertebrate cells activates K+-Cl- cotransporters of the KCC family to alleviate osmotic pressure imbalances. We aim to determine structures of KCCs in inactive and active conformations and in the presence of pharmacological modulators to understand mechanisms of ion movement and regulation in this transporter family.
Aim 3: Determine the structural basis for the function of the cochlear amplifier Prestin.
The exquisite sensitivity and frequency selectivity of mammalian hearing relies on active amplification of sound energy. This is achieved through the activity of a unique motor protein in outer hair cells, Prestin. We aim to determine structures of Prestin in different functional states to understand the molecular basis of its activity in cochlear amplification.
Project Details
Start Date
2019-01-14
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members