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Structure and gating mechanism of the acetylcholine receptor pore

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					Structure and gating mechanism
of the acetylcholine receptor pore
        Acetylcholine receptor
• Important in transmitting messages from neuron to
  neuron
• Is a excitatory neurotransmitter
• Acetylcholine is stored in vesicles at the end of a
  neuron
• When the right signal comes along, it causes the
  release of acetylcholine into the synaptic cleft
• Here it binds to the acetylcholine receptor and
  which will allow for further transmission of the
  signal
Propagation of signal from neuron to neuron via
neurotransmitters
       Acetylcholine receptor
• Classic example of a ligand gated channel
• So it is a ion channel that is ligand gated
• It ultimately leads to an influx of positive
  ions
      Ach Receptor Structure
• 5 transmembrane polypeptides and they are
  2 alpha, 1 beta, 1 delta, and 1 gamma
• Each subunit is made up of 4
  transmembrane alpha helices (helical
  bundle). They are M1-M4
Picture of subunits and M1-M4
      Each helices has features
• M2 is mostly amphipathic while M1, M3,
  and M4 are mostly hydrophobic
• M2 has polar side chains for the most part
  in the middle of the pore and hydrophobic
  backing up against the back of the pore
           Inside the channel
• In the middle of the channel there are 5
  leucine sidechains and these 5 leucine
  sidechains come 1 from each M2 helix
• There function is to protrude into the
  channel and block it
• This is when the channel is in its closed
  conformation and inactivated
Picture inside the channel
    The activated Ach Receptor
• Bulky hydrophobic leucines are removed
  from channel core
• This occurs when Ach binds to the receptor
• Binding causes conformational change,
  twisting of the M2 helices and the leucines
  twist out of the way
   The Activated Ach Receptor
            continued
• The M2 helices now instead of having
  bulky hydrophobic residues now have polar
  residues facing inward and ions can go
  down the channel
Picture of Activated Ach
        Receptor
      Ach Receptor Summary
• Bulky hydrophobic leucine side chains of
  M2 helices close the channel
• Upon activation from Ach binding, the
  leucine side chains twist out of the way and
  now the polar hydrophilic side chains and
  now positive ions can rush through.
  The Paper about Ach Receptor
• Used liquid high helium temperatures
• Resolved protein structure at 4A
• Proposed a mechanism of how the pore
  opens and closes in response to presence or
  absence of Ach
                 Method
• Obtained crystals from Torpedo marmorata
  membranes
• Crystals at first did not yield high
  amplitudes so they adjusted their procedure
  using Fourier transforms to enhance signal
• Used electron imaging to obtain their
  structures
         Signal Transduction
• When cells convert an extracellular signal
  to an intracellular signal that alter the
  behavior of the target cell
Signal Transduction
               Recptors
• Ionotropic         • Metabotropic
• Channel            • Second messenger
• Very fast          • slower
                Receptors
• Ion-channel-linked (AchR) ionotropic
• G-protein linked      metabotropic
• Enzyme-linked         metabotropic
  involves the covalent modification of P to
  serine threonine or tyrosine
           G protein receptor
• 7 transmembrane helices
• Links outside to inside of cell
                G protein
• Made up of three subunits, alpha, beta, and
  gamma ( A heterotrimeric protein)
• The alpha subunit is referred to as the key
  player in relaying the signal
Mechanism of G protein
• Activated G protein leads to the exchange
  of GDP (inactive form) to GTP (active
  form)
• Then this activated subunit will then go and
  activate another protein
             Alpha Subunit
• GTP will bind at a site on this subunit and
  activate it
        Gfrom Transducin
               Beta Subunit
• Built from 7 WD repeats ( motifs that are built
  from tryptophan(W) and aspartate(D)
• Beta Propellar formed by seven subunits made of
  Beta Sheets
                            Pic of Beta Subunit
        Putting it all together
• G does not interact with Gbut the are
  linked by the Gsubunit
• GGinteract
• Forms functional signaling unit
      GEF


GDP         GTP


      GAP
                   Ras protein
•   Monomeric
•   Is active when it has GTP bound
•   Play a role in cell growth and differentiation
•   GTP linked to Ras via Mg2+
Ras protein
Ras protein with GTP linked to it
            via Mg2+