PMID: 22809326

 

    Legend: Sugar

Title : Crystal structure of the conserved domain of the DC lysosomal associated membrane protein : implications for the lysosomal glycocalyx

Abstract :
  1. BACKGROUND: The family of lysosome-associated membrane proteins ( LAMP ) comprises the multifunctional, ubiquitous LAMP-1 and LAMP-2 , and the cell type-specific proteins DC-LAMP ( LAMP-3 ), BAD-LAMP ( UNC-46 , C20orf103 ) and macrosialin ( CD68 )
  2. LAMPs have been implicated in a multitude of cellular processes, including phagocytosis, autophagy, lipid transport and aging
  3. LAMP-2 isoform A acts as a receptor in chaperone-mediated autophagy
  4. LAMP LAMP-2 deficiency causes the fatal Danon disease
  5. The abundant proteins LAMP-1 and LAMP-2 are major constituents of the glycoconjugate coat present on the inside of the lysosomal membrane, the 'lysosomal glycocalyx'
  6. The LAMP family is characterized by a conserved domain of 150 to 200 amino acids with two disulfide bonds
  7. RESULTS: The crystal structure of the conserved domain of human DC-LAMP was solved
  8. It is the first high-resolution structure of a heavily glycosylated lysosomal membrane protein
  9. The structure represents a novel β-prism fold formed by two β-sheets bent by β-bulges and connected by a disulfide bond
  10. Flexible loops and a hydrophobic pocket represent possible sites of molecular interaction
  11. Computational models of the glycosylated luminal regions of LAMP-1 and LAMP-2 indicate that the proteins adopt a compact conformation in close proximity to the lysosomal membrane
  12. The models correspond to the thickness of the lysosomal glycoprotein coat of only 5 to 12 nm, according to electron microscopy
  13. CONCLUSION: The conserved luminal domain of lysosome-associated membrane proteins forms a previously unknown β-prism fold
  14. Insights into the structure of the lysosomal glycoprotein coat were obtained by computational models of the LAMP-1 and LAMP-2 luminal regions