Tag Archives: triglycerides

Answer to Friday’s homework problem

2 days ago you were tasked with the following homework problem: Design a protein to capture cholesterol and triglycerides and insert them between the two leaflets of the standard biological membrane similar but not identical to the plasma membrane.

Why not just tell you Nature/God/Evolution’s solution to the problem?  Because unless you’ve thought about how you’d do it, you won’t appreciate the elegance (and beauty to a chemist) of the solution. 

Lipid droplets are how your cells store cholesterol and triglycerides (neutral fats).  Cholesterol and most fats are made in the lumen of the endoplasmic reticulum.  Then they move through the homework protein and accumulate between the two leaflets of the endoplasmic reticulum membrane, growing into lens-like structures with diameters of 400 to 600 Angstroms before they leave to enter the cytoplasm.  

Well clearly to get them between the sheets so to speak a hole must be formed in the membrane leaflet closest to the lumen, and the hole must have open sides so the cholesterol and triglyceride can escape.  

The protein must also catch the lipids in the lumen.  This is accomplished by an 8 stranded beta sandwich.  The protein must also cross the endoplasmic reticulum membrane so the lipids its caught can escape the sides.  

Like a lot of pores in the membrane (such as ion channels), several copies of the protein must come together to form the hole.  In this case the protein contains two transmembrane alpha helices.  Its hard to count just how many monomers make up the power, but my guess is 11 or so. 

Here’s a picture

 

The transmembrane (TM)alpha helices are in purple, the beta sandwiches are in blue-greem.

8 nm is 8 nanoMeters or 800 angstroms.  The hole looks to be around 30 Angstroms across — plenty of room to allow cholesterol and triglycerides to enter.  When you look at the top view you see that there is plenty of room between the alpha helices within the membrane for the lipids to escape out the side.  

Here’s the reference https://www.pnas.org/content/pnas/118/10/e2017205118.full.pdf

and the citation Proc. Natl. Acad. Sci. vol. 118 pp. e2017205118 ’21.  It’s a beautiful paper

The protein itself is called seipin, and mutations cause a variety of lipodystrophies, some of which have mental retardation.  The paper has some nice molecular dynamics simulations of seipin in action (if you believe that sort of thing). 

Were you smart enough to figure all this out on your own.  Nature/God/Evolution was.  I wasn’t.

Homework assignment

Design a protein to capture cholesterol and triglycerides and insert them between the two leaflets of the standard biological membrane similar but not identical to the plasma membrane. Answer Sunday night 14 March ’21 

I don’t think we fully grasp the chemical ingenuity of Nature when we discover one of its solutions.   Thinking on your homework assignment will give you a chance to appreciate  just how  chemically clever Nature/Evolution/God actually is.