Evolutionary coupling of structural and functional sequence information in the intracellular lipid‐binding protein family

Abstract

We have mined the evolutionary record for the large family of intracellular lipid-binding proteins (iLBPs) by calculating the statistical coupling of residue variations in a multiple sequence alignment using methods developed by Ranganathan and coworkers (Lockless and Ranganathan, Science 1999:286;295-299). The 213 sequences analyzed have a wide range of ligand-binding functions as well as highly divergent phylogenetic origins, assuring broad sampling of sequence space. Emerging from this analysis were two major clusters of coupled residues, which when mapped onto the structure of a representative iLBP under study in our laboratory, cellular retinoic-acid binding protein I, are largely contiguous and provide useful points of comparison to available data for the folding of this protein. One cluster comprises a predominantly hydrophobic core away from the ligand-binding site and likely represents key structural information for the iLBP fold. The other cluster includes the portal region where ligand enters its binding site, regions of the ligand-binding cavity, and the region where the 10-stranded beta-barrel characteristic of this family closes (between strands 1' and 10). Linkages between these two clusters suggest that evolutionary pressures on this family constrain structural and functional sequence information in an interdependent fashion. The necessity of the structure to wrap around a hydrophobic ligand confounds the typical sequestration of hydrophobic side chains. Additionally, ligand entry and exit require these structures to have a capacity for specific conformational change during binding and release. We conclude that an essential and structurally apparent separation of local and global sequence information is conserved throughout the iLBP family.

Structural Basis for Ligand Regulation of the Fatty Acid-binding Protein 5, Peroxisome Proliferator-activated Receptor β/δ (FABP5-PPARβ/δ) Signaling Pathway

“…Although monomers C and D bind LA in the traditional U-conformation, most commonly seen for fatty acids within the binding pockets of iLBP subfamily IV members (FABP3-5 and -7-9), LA adopts a bent or "L" conformation within the pockets of monomers A and B (10,12,23). Overlay of the two ligand configurations from monomers B and C reveals a high degree of positional similarity between the acidic headgroup and carbons 1-10 of the aliphatic chain.…”

“…A member of the iLBP subfamily IV, FABP5 binds a wide array of ligands in a 1:1 ratio, including fatty acids and fatty acid metabolites spanning 10 -22 carbons in length with various saturation states, as well as the vitamin A metabolite all-trans-retinoic acid and numerous synthetic drugs and probes (10,(23)(24)(25). It has also been found to be involved in a range of pathologies, including the metabolic syndrome (26,27), atherosclerosis (28), cancer (29 -33), and potentially certain neurodegenerative diseases (34).…”

The Emerging Functions and Mechanisms of Mammalian Fatty Acid–Binding Proteins

“…However, extensive X-ray crystallographic and nuclear magnetic resonance (NMR) analyses have shown that these proteins display a striking tertiary structural similarity (78). They fold as a slightly elliptical β barrel comprising 10 antiparallel β strands, with two short α helices located between the first and second β strands (Figure 1).…”

Molecular Cloning, Characterization, and mRNA Expression of Intestinal Fatty Acid Binding Protein (<i>I-FABP</i>) in <i>Columba Livia</i>

“…According to the initial tissue from which they are first isolated, members of FABPs are named as followed: Adipocyte-type FABP (A-FABP), Myelin P2 protein (MP2), Testis-type FABP (T-FABP), Epidermaltype (E-FABP), Brain-type (B-FABP), Heart-type (H-FABP), Intestinal-type (I-FABP), Liver basic-type (LB-FABP), Ileal-type (IL-FABP) and Liver-type (L-FABP). Similar with other FABP isoforms, tertiary structure of I-FABP consists of two short α-helices and 10 antiparallel β-strands, which organize into a helical cap and two orthogonal β-sheets (Bernlohr et al, 1997;Marcelino et al, 2006). LCFAs can be bound within the barrel in the central of internal water filled cavity.…”