Membrane Proteins: What Is A Membrane Protein?

A membrane protein is present within the cell by associating with the cell or organelle membrane. They can serve a variety of purposes from allowing ion flux to conducting signals by ligand-binding. Not only do membrane proteins exist within the membrane but also through association with the integral protein or anchoring to the bilayer.

Categories of Membrane Proteins

Extrinsic Membrane Proteins

Proteins can associate weakly with the membrane, through association with intrinsic proteins, weak phospholipid association, monotopic or lipid-anchoring. These associations are often temporary, such as the G-Proteins, which will dissociate when the GPCR is activated to stimulate signalling pathways. Some associations are necessary for intrinsic protein function such as the β-subunit of potassium channels which can promote translocation to the plasma membrane and modulate activity. Association of these proteins can often be disrupted through changes to pH or salt levels.

Lipid anchoring involves the glycolipid structure glycosylphosphatidylinositol (GPI) which acts as an anchor. The palmitoyl chain exists within the membrane while the polar head region covalently binds the carboxy terminus. Cysteine residues also have the potential to anchor to hydrophobic membrane components such as by thioester bond with palmitoyl or farnesyl groups.

Monotopic proteins exist in one layer of the bilayer. The typical requirement of this is an alpha helical region of hydrophobic amino acids. Alternative orientations can also be seen, such as just one face of the helix interacting with the membrane.

Peripheral proteins which associate with integral proteins often recognise particular sequences and have a wide range of possible functions.

Integral Membrane Proteins

An integral membrane protein is one which spans the lipid bilayer. The key property integral membrane proteins possess are sequences of non-polar amino acid, typically 20aa long, so that the protein can be incorporated into the lipid region of the bilayer. This is can be calculated by considering the width of the lipid bilayer of 45Å, and that a turn of an α helix has a height of 5.4Å and consists of 3.6aa. Therefore 30aa are required to span the membrane however only a core sequence must be hydrophobic to exist within the internal lipid region of the membrane.

Integral membrane proteins can be categorised based on the number of transmembrane domains they possess and the orientation. Type 1 proteins are span the membrane once and expose the N-terminus is to the extracellular space. Type 2 proteins are also single pass but expose the C-terminus to the extracellular space.

Other properties of integral membrane proteins will depend on their function. Ion channels may require forming multimers or associating with subunits. Receptors may have post translational modifications to increase ligand specificity.

Molecular Control Of Membrane Proteins

Control of Membrane Proteins

Membrane proteins require complex mechanisms of control and when these are disordered it can result in disease.

Ligands are one mechanism of control, not only for typical receptors such as the insulin receptor or GPCR, but also for ion channels. A ligand can act in a multitude of ways, like with enzymes: agonist, antagonist, partial agonist, competitive antagonist, non-competitive antagonist and uncompetitive antagonist. Ligands can be naturally secreted by cells and may act locally (paracrine and autocrine) or have a widespread effect (endocrine). Ligands are also developed synthetically for drug development allowing the manipulation of membrane proteins to relieve pathological symptoms. The ligand will be recognised by a specific region of the membrane protein and cause a conformational change upon binding. This conformational change in some way leads to the activation or inhibition of the protein.

The conformational change may be that the receptor can then dimerise and thus stimulate a signalling cascade such as with the tyrosine kinase receptors, for example the insulin, IGFs and growth hormone receptors. When the appropriate ligand binds to the receptor, it allows the receptor to dimerise and undergo autophosphorylation of the intracellular C-terminus.

Alternative methods of membrane protein activation include pH sensitivity, voltage gating, ion sensitivity, phosphorylation, "ball and chain" and many more so that the protein can be activated or inactivated under the appropriate conditions.

Interactions of Intrinsic and Extrinsic Membrane Proteins

Intrinsic membrane proteins often rely on extrinsic proteins for their function as well as developing varying activation sensitivity. GPCR, for example, utilise G Proteins to exert their effect upon activation. When the GPCR is activated, a conformational change allows the G Protein to exchange GDP for GTP and consequently can relay the signal.

Extrinsic proteins can promote expression of intrinsic proteins at the cell surface by the obscuring of retention sequences. Evidence of this is seen in potassium channels, such as Kir and its subunit Sur. The intracellular subunits can also promote cell surface expression by preventing ubiquitination, such as the CaV β subunit, which inhibits ubiquitination by RFP2. It is also theorised that the β subunits of ion channels may actually contain a exportation sequence to promote trafficking to the membrane.

Extrinsic proteins can also be vital for creating ion channel diversity. This may in part be for tissue specificity or modulating inactivation. For example, Kv1 can be inactivated by β1 but not β2.

Additional Resources

Basic Texts:

  • Essential Cell Biology by Bruce Alberts, Dennis Bray, Karen Hopkin and Alexander Johnson
  • Biochemistry by Jeremy M. Berg, John L. Tymoczko and Lubert Stryer

Useful Reviews:

    • Catterall W.A. 2010, 'Ion Channel Voltage Sensors: Structure, Function, And Pathophysiology', Neuron, 67, , pp. 915-928.
    • Dolphin A.C. 2009, 'Calcium Channel Diversity: Multiple Roles Of Calcium Channel Subunits', Curr Opin Neurobiol, 19, , pp. 237-244.
    • Pongs O.& Schwarz J.R. 2010, 'Ancillary Subunits Associated With Voltage-Dependent K+ Channels.', Physiol Rev, 90, , pp. 755-796.

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