Research Article: Different modes of barrel opening suggest a complex pathway of ligand binding in human gastrotropin

Date Published: May 10, 2019

Publisher: Public Library of Science

Author(s): Zita Harmat, András L. Szabó, Orsolya Tőke, Zoltán Gáspári, Pratul K. Agarwal.


Gastrotropin, the intracellular carrier of bile salts in the small intestine, binds two ligand molecules simultaneously in its internal cavity. The molecular rearrangements required for ligand entry are not yet fully clear. To improve our understanding of the binding process we combined molecular dynamics simulations with previously published structural and dynamic NMR parameters. The resulting ensembles reveal two distinct modes of barrel opening with one corresponding to the transition between the apo and holo states, whereas the other affecting different protein regions in both ligation states. Comparison of the calculated structures with NMR-derived parameters reporting on slow conformational exchange processes suggests that the protein undergoes partial unfolding along a path related to the second mode of the identified barrel opening motion.

Partial Text

Gastrotropin (also known as ileal bile acid-binding protein (I-BABP) or fatty acid-binding protein 6 (FABP6)) [1] is involved in the enterohepatic circulation of bile salts. Being synthetsized in the liver from cholesterol, bile salts are secreted into the proximal small intestine via the gall bladder and then efficiently recycled blood via the hepatic portal circulation [2–3]. This recycling process ensures that only a small amount of bile salts needs to be synthesised de novo. Gastrotropin is thought to play a role in this recyclinc process via binding interactions occurring within the absorptive epithelial cells of the distal ileum [4–5] and has an important role in cholesterol homeostasis [1,6].

We have generated structural ensembles that are in agreement with available NMR parameters reporting on the structure and fast time-scale dynamics of human gastrotropin. The two types of barrel opening identified are in agreement with previous observations of the iLBP family. We propose a refined model of ligand entry that is compatible with the portal hypothesis, namely, that the structural transition from the apo to the holo state, termed Type I opening, proceeds along an indirect route involving partial unfolding of the helical cap structure. In our model this unfolding is related to and facilitated by another mode of barrel opening, termed Type II, that is present in both the apo and holo states.




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