Lysosomal membrane glycoproteins bind cholesterol and contribute to lysosomal cholesterol export.
LAMP1 and LAMP2 proteins are highly abundant, ubiquitous, mammalian proteins that line the lysosome limiting membrane, and protect it from lysosomal hydrolase action. LAMP2 deficiency causes Danon's disease, an X-linked hypertrophic cardiomyopathy. LAMP2 is needed for chaperone-mediated autophagy, and its expression improves tissue function in models of aging. We show here that human LAMP1 and LAMP2 bind cholesterol in a manner that buries the cholesterol 3β-hydroxyl group; they also bind tightly to NPC1 and NPC2 proteins that export cholesterol from lysosomes. Quantitation of cellular LAMP2 and NPC1 protein levels suggest that LAMP proteins represent a significant cholesterol binding site at the lysosome limiting membrane, and may signal cholesterol availability. Functional rescue experiments show that the ability of human LAMP2 to facilitate cholesterol export from lysosomes relies on its ability to bind cholesterol directly.
Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.
Jian
J
Li
Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.
Suzanne R
0000-0002-6462-984X
SR
Pfeffer
D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism*; D051907:Lysosomal Membrane Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D011485:Protein Binding; D033921:Vesicular Transport Proteins; D052118:Lysosomal-Associated Membrane Protein 1
D002352:Carrier Proteins; D002784:Cholesterol; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C497811:LAMP2 protein, human; C106881:NPC1 protein, human; C104585:NPC2 protein, human
Niemann Pick disease; biochemistry; cell biology; cholesterol; glycocalyx; human; lysosome membrane
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