Secreted progranulin is a homodimer and is not a component of high density lipoproteins (HDL).
Progranulin is a secreted glycoprotein, and the GRN gene is mutated in some cases of frontotemporal dementia. Progranulin has also been implicated in cell growth, wound healing, inflammation, and cancer. We investigated the molecular nature of secreted progranulin and provide evidence that progranulin exists as a homodimer. Although recombinant progranulin has a molecular mass of ∼85 kDa by SDS-PAGE, it elutes in fractions corresponding to ∼170-180 kDa by gel-filtration chromatography. Additionally, recombinant progranulin can be intermolecularly cross-linked, yielding a complex corresponding to a dimer (∼180 kDa), and progranulins containing different epitope tags physically interact. In plasma, progranulin similarly forms complexes of ∼180-190 kDa. Although progranulin partially co-fractionated with high density lipoproteins (HDL) by gel-filtration chromatography, we found no evidence that progranulin in mouse or human plasma is a component of HDL either by ultracentrifugation or by lipid binding assays. We conclude that circulating progranulin exists as a dimer and is not likely a component of HDL.
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158.
Andrew D
AD
Nguyen
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158.
Thi A
TA
Nguyen
Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Basar
B
Cenik
Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Gang
G
Yu
Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390; Department of Neuroscience, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
Joachim
J
Herz
Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut 06520.
Tobias C
TC
Walther
Center for Lipid and Arteriosclerosis Science, University of Cincinnati, Cincinnati, Ohio 45237.
W Sean
WS
Davidson
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158,; Departments of Medicine and Biochemistry and Biophysics, University of California, San Francisco, California 94158. Electronic address: bfarese@gladstone.ucsf.edu.
Robert V
RV
Farese
D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000097:blood* / Q000302:isolation & purification; D051379:Mice; D018345:Mice, Knockout; D000077153:Progranulins; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism
D016632:Apolipoprotein A-I; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008075:Lipoproteins, HDL; D000077153:Progranulins; D011994:Recombinant Proteins