Structure of bacterial phospholipid transporter MlaFEDB with substrate bound

Area of Science:

• Microbiology
• Structural Biology
• Biochemistry

Background:

• Phospholipid transport is vital for maintaining the outer membrane barrier in double-membraned bacteria.
• This barrier is essential for bacterial virulence and antibiotic resistance.
• The Mla (multiple lipid-binding) system, including the MlaFEDB ABC transporter, is implicated in phospholipid trafficking.

Purpose of the Study:

• To determine the structure of the inner-membrane MlaFEDB complex.
• To elucidate the mechanism of phospholipid transport mediated by MlaFEDB.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structure of MlaFEDB.
• The structure was resolved at 3.05 Å resolution.

Main Results:

• The cryo-EM structure of MlaFEDB was determined, revealing distant evolutionary relationships to LPS, MacAB, and eukaryotic ABCA/ABCG transporters.
• A continuous transport pathway was identified from the MlaE substrate-binding site through MlaD to the periplasm.
• Two phospholipid molecules were found bound to MlaFEDB, suggesting multi-substrate transport per cycle.

Conclusions:

• The structure provides mechanistic insights into substrate recognition and transport by MlaFEDB.
• This work advances our understanding of phospholipid homeostasis and outer membrane biogenesis in bacteria.
• The findings may have implications for developing new antimicrobial strategies targeting bacterial membrane integrity.