A Systematic Investigation of Structure/Function Requirements for the Apolipoprotein A-I/Lecithin Cholesterol Acyltransferase Interaction Loop of High-density Lipoprotein.

The Journal of Biological Chemistry
Xiaodong GuStanley L Hazen

Abstract

The interaction of lecithin-cholesterol acyltransferase (LCAT) with apolipoprotein A-I (apoA-I) plays a critical role in high-density lipoprotein (HDL) maturation. We previously identified a highly solvent-exposed apoA-I loop domain (Leu(159)-Leu(170)) in nascent HDL, the so-called "solar flare" (SF) region, and proposed that it serves as an LCAT docking site (Wu, Z., Wagner, M. A., Zheng, L., Parks, J. S., Shy, J. M., 3rd, Smith, J. D., Gogonea, V., and Hazen, S. L. (2007) Nat. Struct. Mol. Biol. 14, 861-868). The stability and role of the SF domain of apoA-I in supporting HDL binding and activation of LCAT are debated. Here we show by site-directed mutagenesis that multiple residues within the SF region (Pro(165), Tyr(166), Ser(167), and Asp(168)) of apoA-I are critical for both LCAT binding to HDL and LCAT catalytic efficiency. The critical role for possible hydrogen bond interaction at apoA-I Tyr(166) was further supported using reconstituted HDL generated from apoA-I mutants (Tyr(166) → Glu or Asn), which showed preservation in both LCAT binding affinity and catalytic efficiency. Moreover, the in vivo functional significance of NO2-Tyr(166)-apoA-I, a specific post-translational modification on apoA-I that is abundant withi...Continue Reading

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Citations

Aug 17, 2016·Biochemistry·Chase A Brisbois, Jennifer C Lee
Feb 14, 2018·Journal of Lipid Research·Marco G CasteleijnArtturi Koivuniemi
May 19, 2018·Journal of Lipid Research·Allison L CookeW Sean Davidson
May 2, 2018·Proceedings of the National Academy of Sciences of the United States of America·Mohsen PourmousaRichard W Pastor
Jul 3, 2021·International Journal of Molecular Sciences·Herman E PopeijusJogchum Plat

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