Acetylcholine Receptor Pore

Introduction

Acetylcholine receptor pore is a member of the transmitter-gated ion pores, and can be found spanning the postsynaptic membranes at the nerve to muscle synapse. This pore allows ion flow into the cell as acetylcholine enters the ligand-binding domain of the receptor, which then initiates an action potential. There are two main functional domains of the receptor protein, an extracellular domain and a transmembrane domain. There are five subunits of the membrane portion of the protein, which are termed A, B, C, D, and E. Subunit D is an identical repeat of A, and they both provide the connection between the membrane-spanning and the extracellular domains. Each of the five subunits has four alpha-helices that span the membrane, three of which are (membrane) lipid-facing while the fourth is pore-facing. The five pore-facing helices from each subunit make up the actual pore, and are responsible for the gating function of the protein. The structure shown here contains the 5 pore-forming helices from the 5 subunits.

Extracellular Ligand Binding Domain

As described in the introduction there are extracellular portions of the protein that consist mostly of beta sheets and are not included in this modeling page. On binding acetylcholine, a conformational change occurs which is then transmitted to the inner five helices. This change in conformation results in the opening of the pore through the rotation of the inner (pore-facing) helices within the membrane portion of the protein.

For more information see Biochemistry Online: Chapter 9B - Signal Transduction - Neurochemistry

Wireframe

Spacefill viewed along membrane plane

Spacefill facing membrane plane (pore clearly evident)

Chain A (Red)

Chain B (Green)

Chain C (Blue)

Chain D (White)

Chain E (Yellow)

Gate Residues

The pore is cation selective and only allows hydrated sodium or potassium ions to pass through. The middle of the pore is constricted due to the small separation of the helices and to the presence of bulky hydrophobic side chains. The most kinked part of the passage represents the gate. The inner helices are closely identical, and the equivalent surfaces of the homologous residues from each helix form ‘levels’ through the entire passage. The gate is made up of identical interactions between residues of the five helices, the main ones being hydrophobic interactions between phenylalanine and valine or isoleucine, and that of leucine with alanine or serine. These interactions create a tight hydrophobic girdle around the pore, which presents a barrier to the flow of hydrated ions across the membrane. Hydrated ions are not able to pass this gate, unless the conformational change has taken place, in which the inner helices were rotated and the hydrophobic interactions between the residues that make up the gate were disrupted. Be sure to select the five inner helices model, select charged atoms, then hydrophobic atoms, and lastly the gate atoms.

Gate Residues facing membrane plane

Acetylcholine binding domain (2BG)