1 / 25

Apolipoproteins

Apolipoproteins. Lipoprotein complexes. Lipoprotein complexes Triaglycerol lipid droplets Cholesterol esters Phospholipids Apolipoproteins. Lipoproteins. Chylomicrons High density lipoproteins, HDL Intermediate density lipoproteins, IDL Low density lipoproteins, LDL

jadon
Download Presentation

Apolipoproteins

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Apolipoproteins

  2. Lipoprotein complexes • Lipoprotein complexes • Triaglycerol lipid droplets • Cholesterol esters • Phospholipids • Apolipoproteins

  3. Lipoproteins • Chylomicrons • High density lipoproteins, HDL • Intermediate density lipoproteins, IDL • Low density lipoproteins, LDL • Very low density lipoproteins, VLDL

  4. Apolipoproteins • ApoA-I, II and IV • ApoB-48 and 100 • ApoC-I, II and III • ApoD • Cholesterol ester transfer protein • ApoE • ApoH

  5. Closer look Apolipoprotein A-I Apolipoprotein A-II HDL and enzyme LCAT Atherosclerosis ?

  6. Apolipoprotein A-I • ApoA-I synthesized in intestine and liver • Associated with chylomicrons and HDL

  7. A look at the structure of ApoA-I • PDB ID 1AV1 • Four alpha helical horseshoe shaped molecules that in the crystal form create a tightly associated elliptical ring.

  8. Horseshoe shaped pseudo-continuous amphipathic alpha helix Punctuated by kinks of regularly spaced proline residues Monomer of ApoA-I

  9. Dimer of ApoA-I • Consists of two monomers arranged antiparallel

  10. Dimer of ApoA-I • One face of the dimer is hydrophilic (pink) the other face is hydrophobic (blue)

  11. Tetramer of ApoA-I • In the crystal form two dimers join in an antiparallel fashion to form an elliptical tetrameric ring. • This is not the structure that binds to lipids because hydrophobic side chains are hidden

  12. Proposed ApoA-I lipid binding • Binds as dimer • Elliptical shape -> circular shape • By adjustment of interhelical kinks and bends • Dimer wraps around lipid like a belt • Lipid bound structure has not been solved

  13. Apolipoprotein A-II • Exchangeable apolipoprotein • Associated with HDL

  14. Structure of lipid free ApoA-II • PDB ID 1L6K • Monomer • Alpha helices punctuated by proline residues, but less uniformly than in ApoA-I • Dimer • Side to side packing of two monomers joined by a salt bridge • Contains three hydrophobic patches

  15. Tetramer of ApoA-II • Side to side packing of two dimers shields hydrophobic patches (cyan), when lipids not present Top view of 3 tetramers Side view of 3 tetramers

  16. Lipid bound ApoA-II, ApoA-II-BOG • PDB ID 1L6L • ApoA-II with beta-octylglucopiranoside • Head to tail packing in the tetramers, dimers held together by hydrogen bonds and polar interactions between Gln77 and Ala2 and Lys3 • Curved confirmation due to residues 31-39

  17. ApoA-II-BOG ApoA-II-BOG, regions enabling flexibility highlighted in red. Close up of molecules involved in head to tail packing shown

  18. ApoA-I and II bind to HDL • HDL, highest density lipoprotein due to it’s protein lipid ratio • Contains almost no cholesterol or cholesterol esters when synthesized • Obtains cholesterol esters from cholesterol by the HDL associated enzyme, lecithin: cholesterol acyltransferase (LCAT)

  19. LCAT • LCAT is synthesized in the liver • LCAT makes cholesterol esters from free cholesterol found in chylomicron remnants and VLDL remnants • LCAT transfers a fatty acid from the C-2 position of lecithin to the C-3-OH of cholesterol, generating a cholesterol ester and lysolecithin • The action of LCAT requires interaction with ApoA-I

  20. ApoA-I and LCAT • ApoA-I activates LCAT by binding to HDL • increasing helical content of ApoA-I • Orients the protein to provide necessary contacts with enzyme • ApoA-I interacts with LCAT through positively charged residues on the side chains of the ApoA-I helices

  21. ApoA-II displaces ApoA-I • ApoA-II can completely displace ApoA-I from HDL • Two molecules of ApoA-II displace one of ApoA-I • Flexibility of ApoA-II allows displacement onto any size HDL which ApoA-I is bound to • ApoA-II forms a more stable complex with HDL • Head to tail interactions • C terminal helix more hydrophobic than any helix from ApoA-I • ApoA-II does not activate LCAT

  22. atherosclerosis • HDL and ApoA-I negatively correlated with atherosclerosis • ApoA-II positively correlated with atherosclerosis • Deposits of fat and cholesterol building up in lining of arteries • Atherosclerosis->cardiovascular heart disease

  23. How HDL prevents Atherosclerosis • HDL transports cholesterol from peripheral tissues to liver for catabolism • LCAT converts cholesterol into cholesterol esters • ApoA-I needs to be bound to HDL to activate LCAT

  24. Conclusion ApoA-I HDL Activate LCAT Helps prevent atherosclerosis ApoA-I ApoA-II Does not activate LCAT Leads to higher Levels of Atherosclerosis HDL

  25. References • The medical biochemistry page http://www.indstate.edu/thcme/mwking/lipoproteins.html • Molecular biochemsitry, Joyce J. Diwan http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/lipoprot.htm • Bolanos-Garcia et al., 2003.  On the structure and function of apolipoproteins: more than a family of lipid-binding proteins. Progress in Biophysics and Molecular Biology. 83:47-68. • Borhani et al., 1997. Crystal structure of truncated human apolipoprotein A-I suggests a lipid-bound conformation. Proc. Natl. Acad. Sci. 94:12291-12296. • Kumar et al., 2002. Structures of Apolipoprotein A-II and a lipid-surrogate complex provide insights into Apolipoprotien-lipid interactions. Biochemistry. 41:11681-11691. • Mahley et al. 1984. Plasma lipoproteins: apolipoprotein structure and function. Journal of lipid research. 25:1277-1294.

More Related