Bulky hydrophobic side chains in the β1-sandwich of microsomal triglyceride transfer protein are critical for the transfer of both triglycerides and phospholipids

• DOI: 10.1016/j.jbc.2024.105726
• Publication Date: 2024-02-05T17:17:52Z
• Authors: Narasimha Anaganti; Swati Valmiki; Rosario Recacha; Shahidul Islam; Steven Farber; Lloyd Ruddock; M. Mahmood Hussain
• Keywords: Side chain

Hyperlipidemia predisposes individuals to cardiometabolic diseases, the most common cause of global mortality. Microsomal triglyceride transfer protein (MTP) transfers multiple lipids and is essential for assembly apolipoprotein B-containing lipoproteins. MTP inhibition lowers plasma but causes lipid retention in liver intestine. Previous studies suggested two domains that specific (TG) not phospholipid (PL) can lower without significant tissue accumulation. However, how different involved these activities are unknown. Here, we tested a hypothesis β-sandwich TG PL. Mutagenesis charged amino acids β2-sandwich had no effect on PL activity indicating they critical. In contrast, with bulky hydrophobic side chains β1-sandwich were critical both activities. Substitutions residues smaller or positive charges reduced, whereas negatively severely attenuated These point domain enriched acids. Furthermore, observed strong correlation mutants respect loss activities, again implicating binding site MTP. We propose targeting areas other than identified might reduce causing cellular retention.