Water-mediated recognition of simple alkyl chains by heart-type fatty-acid-binding protein.

Shigeru Matsuoka,Eiichi Mizohata,Mika Hirose,Daisuke Matsuoka,Michio Murata,Hanako Ishida,Satoshi Murakami,Tsuyoshi Inoue,Toshiaki Hara,Sébastien Lethu,Osamu Ichihara,Hikaru Ano,Shigeru Sugiyama,S Roy Kimura

doi:10.1002/anie.201409830

Abstract

Long-chain fatty acids (FAs) with low water solubility require fatty-acid-binding proteins (FABPs) to transport them from cytoplasm to the mitochondria for energy production. However, the precise mechanism by which these proteins recognize the various lengths of simple alkyl chains of FAs with similar high affinity remains unknown. To address this question, we employed a newly developed calorimetric method for comprehensively evaluating the affinity of FAs, sub-Angstrom X-ray crystallography to accurately determine their 3D structure, and energy calculations of the coexisting water molecules using the computer program WaterMap. Our results clearly showed that the heart-type FABP (FABP3) preferentially incorporates a U-shaped FA of C10–C18 using a lipid-compatible water cluster, and excludes longer FAs using a chain-length-limiting water cluster. These mechanisms could help us gain a general understanding of how proteins recognize diverse lipids with different chain lengths.

Highlights

Long-chain fatty acids (FAs) with low water solubility require fatty-acid-binding proteins (FABPs) to transport them from cytoplasm to the mitochondria for energy production
As reported for FABP3, one long-chain fatty acids (LCFAs) molecule in a U-shape is accommodated in the binding cavity together with about 13 ordered water molecules.[5]
These observations suggest that the U-shape conformation of bound FA is critical for the incorporation of FAs with different chain lengths into the binding site of FABP3 and the other FABPs, and raise an intriguing question as to how the proteins do this by using a rigid b-clam architecture and ordered water molecules in the pocket

Summary

Introduction

Long-chain fatty acids (FAs) with low water solubility require fatty-acid-binding proteins (FABPs) to transport them from cytoplasm to the mitochondria for energy production. These observations suggest that the U-shape conformation of bound FA is critical for the incorporation of FAs with different chain lengths into the binding site of FABP3 and the other FABPs, and raise an intriguing question as to how the proteins do this by using a rigid b-clam architecture and ordered water molecules in the pocket.

Results

Conclusion