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). 
LAMPs have been implicated in a multitude of cellular processes, including 
phagocytosis, autophagy, lipid transport and aging. LAMP-2 isoform A acts as a 
receptor in chaperone-mediated autophagy. LAMP-2 deficiency causes the fatal 
Danon disease. 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'. The LAMP family is characterized by a conserved domain 
of 150 to 200 amino acids with two disulfide bonds.
RESULTS: The crystal structure of the conserved domain of human DC-LAMP was 
solved. It is the first high-resolution structure of a heavily glycosylated 
lysosomal membrane protein. The structure represents a novel β-prism fold formed 
by two β-sheets bent by β-bulges and connected by a disulfide bond. Flexible 
loops and a hydrophobic pocket represent possible sites of molecular 
interaction. 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. The models correspond to the thickness of 
the lysosomal glycoprotein coat of only 5 to 12 nm, according to electron 
microscopy.
CONCLUSION: The conserved luminal domain of lysosome-associated membrane 
proteins forms a previously unknown β-prism fold. Insights into the structure of 
the lysosomal glycoprotein coat were obtained by computational models of the 
LAMP-1 and LAMP-2 luminal regions.