The cation channel mucolipin-1 is a bifunctional protein that facilitates membrane remodeling via its serine lipase domain.
Phospholipase modulators have been shown to affect the topology of lipid bilayers and the formation of tubulo-vesicular structures, but the specific endogenous phospholipases involved have yet to be identified. Here we show that TRPML1 (MLN1), a Ca(2+)-permeable channel, contributes to membrane remodeling through a serine lipase consensus domain, and thus represents a novel type of bifunctional protein. Remarkably, this serine lipase active site determines the ability of MLN1 to generate tubulo-vesicular extensions in mucolipin-1-expressing oocytes, human fibroblasts and model membrane vesicles. Our demonstration that MLN1 is involved in membrane remodeling and the formation of extensions suggests that it may play a role in the formation of cellular processes linked to the late endosome/lysosome (LE/L) pathway. MLN1 is absent or mutated in patients with mucolipidosis IV (MLIV), a lysosomal disorder with devastating neurological and other consequences. This study provides potential insight into the pathophysiology of MLIV.
Division of Endocrinology, Diabetes and Hypertension and Membrane Biology Program, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. jlaplante@rics.bwh.harvard.edu
Janice M
JM
LaPlante
John L
JL
Falardeau
Edward M
EM
Brown
Susan A
SA
Slaugenhaupt
Peter M
PM
Vassilev
D000818:Animals; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism*; D005347:Fibroblasts / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D050576:Membrane Fusion Proteins / Q000235:genetics / Q000378:metabolism; D009081:Mucolipidoses / Q000201:enzymology; D009154:Mutation; D017434:Protein Structure, Tertiary; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D050051:Transient Receptor Potential Channels; D014982:Xenopus laevis
C416674:MCOLN1 protein, human; D050576:Membrane Fusion Proteins; D050053:TRPM Cation Channels; D050051:Transient Receptor Potential Channels; D008049:Lipase
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