Born Slippy; Protein-Lipid interactions around the human body

Published on February 6th, 2019

There are many proteins which interact with lipids in vivo, in complex relationships that have crucial impacts on organism health.

Recent studies on α-synuclein and its link to Parkinson’s disease include observing its binding with lipids, but many protein-lipid interactions are not disease related, and simply play a role in normal biochemical functions.

Here are a few interesting protein-lipid interactions from around the human body that play vital parts in healthy function.

Pulmonary Surfactant Proteins

Pulmonary Surfactant is a 90% lipid and 10% protein mix (along with trace amounts of carbohydrates) found in the lungs.

The main role is to reduce surface tension at the air-liquid interface in the alveolae. This avoids collapse on expiration and allows expansion on inhalation. It is also important in the transfer of surface active molecules from tissues into the interface.

The four proteins present are known as SP-A, SP-B, SP-C and SP-D (SP here standing for “Surfactant-associated Protein”).

  1. SP-A exists as an oligomer of six trimers and binds mannose, allowing it to act in a range of immune functions including bacteria clearance and viral neutralization.
  2. SP-B is involved in determining the structure of tubular myelin, the stability and speed of spreading and the recycling of phospholipids.
  3. SP-C is highly hydrophobic, so much so that handling it for detailed study has proven difficult. One study comments that it is one of the most non-polar naturally occurring polypeptides known, and that “much remains to be learned about the molecular functions”.
  4. SP-D is very similar in structure to SP-A, but is present at far lower levels (around 10 fold). It plays a major role in surfactant turnover and homeostasis

Read more:

  • Protein–lipid interactions and surface activity in the pulmonary surfactant system, Serrano et al., Chemistry and Physics of Lipids, 2006
  • Function and regulation of expression of pulmonary surfactant-associated proteins, Weaver et al., Biochemical Journal, 1991
  • Structure and properties of surfactant protein C, Johansson, BBA Molecular Basis of Disease, 1998


The class of human exchangeable apolipoproteins (apo) includes a range of specific variants, all of which interact with lipids.

These have been found to undergo significant structural change upon binding lipids. ApoA-I was found to have two distinct domains in its lipid-free state; a helix bundle and a disordered structure. In a two-step binding process the bundle opens to allow helix-lipid interactions.

While it has been suggested these proteins play a role in lipid transport and metabolism, more recent work argues that they could function as ion channels and play a role in triggering cell death.

What we do know is that deficiency in various apo’s results in a range of conditions from atherosclerosis (plaque build up in arteries), tubo-eruptive xanthomas (yellow skin deposits rich in cholesterol) and other cardiovascular diseases.

Read more:

  • Domain structure and lipid interaction in human apolipoproteins A-I and E, a general model, Saito et al., Journal of Biological Chemistry, 2003
  • The function of apolipoproteins L, Vanhollebeke et al., Cellular and Molecular Life Sciences, 2006
  • Familial apolipoprotein E deficiency, Schaefer et al., The Journal of Clinical Investigation, 1986

Membrane proteins

Of course no mention of protein-lipid interactions would be complete without considering the huge class of membrane proteins. This varied and extensive group account for about 20-30% of a typical organism’s genome, but their complex extraction and purification mean that less than 1% of known high-resolution structures are membrane proteins.

Membrane protein-lipid interactions can be broadly split into three classes;

  1. Shells of lipids bound to the protein surface (“Annular lipids”)
  2. Lipids bound in cavities and clefts of a protein surface (“non-annular surface lipids”)
  3. Lipids found within the protein or protein complex (“integral protein lipids”)

However, the role of lipid interactions on these proteins is as varied as the proteins functions; with structural stability, folding, assembly and oligomerization and binding and function all being found in different proteins to hinge on lipid interactions.

Read more:

  • Specific protein–lipid interactions in membrane proteins, Hunte, Biochemical Society Transactions, 2005


The metalloprotein neuroglobin (Ngb) is linked to protecting neurons and myocardial cells during times of oxidative stress. Only discovered in 2000, Ngb shares common features with other globin proteins – for example its structure (eight α-helices in a two-layer structure) and its high temperature stability (it remains functional to 90 °C).

A surprising feature of Ngb is that although it usually exists as an intracellular protein, during times of stress in a cell it is recruited into “lipid rafts” – membrane domains rich in cholesterol and sphingolipids which are resistant to detergents and linked to signal transduction. These rafts have been found in organelle membranes as well as plasma membranes.

While the lipid raft interactions have been documented, the precise role of Ngb is still debated and could be quite varied. In resting neurons its low concentration (~ 1 µM) suggests it plays an enzymatic or signaling role, whereas the high concentration (100-200 µM) seen in the optic nerve could make it useful in O2 supply or diffusion.

Read more:

  • Neuroglobin: From structure to function in health and disease, Ascenzi et al., Molecular Aspects of Medicine, 2016
  • Human Neuroglobin Functions as an Oxidative Stress-responsive Sensor for Neuroprotection, Watanabe et al., The Journal of Biological Chemistry, 2012

Studying protein-lipid interactions

The uncertainty surrounding the precise purpose and function of some of these protein-lipid relationships, combined with the observation of disease states resulting from these interactions going wrong, serves to illustrate that further work is needed to develop our understanding.

Techniques including circular dichroism or microfluidic diffusional sizing can be employed to analyze protein-lipid interactions, but reviews on the topic remark that systematic investigation is still needed.

Protein scientists should consider the many and varied affects of lipids, and stay up to date with technological developments in analyzing these intricate and complex relationships.

Read more:

  • The systematic analysis of protein-lipid interactions comes of age, Saliba et al., Nature Reviews Molecular Cell Biology, 2015