Evolutionary mix-and-match with MFS transporters

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Major facilitator superfamily (MFS) transport proteins are essential membrane proteins found in all cells, constituting a significant portion of prokaryotic transporters.
• These transporters utilize electrochemical gradients, often proton gradients, to move a wide array of substrates across membranes.
• MFS proteins share conserved structural features, including a central hydrophilic cavity and 12 transmembrane helices, suggesting a common evolutionary pathway.

Purpose of the Study:

• To investigate the evolutionary relationships and structural homologies between different MFS transporters.
• To explore the potential for shared structural motifs and functional sites despite low sequence homology.
• To understand the origins of sequence diversity within the MFS.

Main Methods:

• Comparative analysis of structural symmetry motifs between Escherichia coli fucose permease (FucP) and lactose permease (LacY).
• Mapping and comparison of point mutation locations in FucP and LacY to identify conserved functional regions.
• Sequence alignment focusing on functional sites, including substrate and ion-binding regions.

Main Results:

• Rearrangement of structural symmetry motifs in FucP reveals significant homology to LacY.
• Mutational data supports the homology between FucP and LacY, particularly in conserved functional regions.
• Homologies are identified between sugar- and H(+)-binding sites in FucP and LacY, challenging conventional linear sequence alignment interpretations.

Conclusions:

• FucP and LacY likely evolved from common primordial helix-triplets, with functional segments assembling in varied orders.
• This evolutionary model provides a parsimonious explanation for the extensive sequence diversity observed within the MFS.
• The findings highlight the importance of structural and functional site analysis in understanding transporter evolution.