LMBD1 Protein Serves as a Specific Adaptor for Insulin Receptor Internalization

Tseng, Linda Tzu-Ling; Lin, Chieh-Liang; Tzen, Kai-Yuan; Chang, Shih‐Chieh; Chang, Shan‐Chwen

doi:10.1074/jbc.m113.479527

Cited by 32 publications

(34 citation statements)

References 31 publications

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“…There are discrepancies within the literature concerning the cellular location of both LMBD1 and ABCD4. LMBD1 has been shown to localize to the lysosome (5), although a later study using surface protein biotinylation found that ϳ3-4% of LMBD1 is located at the plasma membrane (15). We provide additional evidence of lysosomal localization via colocalization of LMBD1 with LAMP1 and LysoTracker using confocal microscopy.…”

Section: Potential Cellular Location Of the Lmbd1-abcd4 Complexmentioning

confidence: 63%

“…By homology to LIMR, which binds and internalizes lipocalins, small secreted proteins that bind protoporphin IX among other ligands (14), a receptor/transporter role has been suggested (5). Furthermore, and of as yet unknown significance, a recent study suggested a small percentage (ϳ3.4%) of LMBD1 is retained at the plasma membrane and is important for insulin receptor internalization (15). Thus far all 16 patients with recessive mutations in LMBRD1 have presented with the cblF type disorder (5, 16 -19) without apparent glucose metabolism dysregulation.…”

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confidence: 99%

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Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1

Fettelschoss

Burda

Sagné

et al. 2017

Journal of Biological Chemistry

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Vitamin B (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes and result in the cobalamin metabolism disorders cblF and cblJ. We report a new (fifth) patient with the cblJ disorder who presented at 7 days of age with poor feeding, hypotonia, methylmalonic aciduria, and elevated plasma homocysteine and harbored the mutations c.1667_1668delAG [p.Glu556Glyfs*27] and c.1295G>A [p.Arg432Gln] in the gene. Cbl cofactor forms are decreased in fibroblasts from this patient but could be rescued by overexpression of either ABCD4 or, unexpectedly, LMBD1. Using a sensitive live-cell FRET assay, we demonstrated selective interaction between ABCD4 and LMBD1 and decreased interaction when ABCD4 harbored the patient mutations p.Arg432Gln or p.Asn141Lys or when artificial mutations disrupted the ATPase domain. Finally, we showed that ABCD4 lysosomal targeting depends on co-expression of, and interaction with, LMBD1. These data broaden the patient and mutation spectrum of cblJ deficiency, establish a sensitive live-cell assay to detect the LMBD1-ABCD4 interaction, and confirm the importance of this interaction for proper intracellular targeting of ABCD4 and cobalamin cofactor synthesis.

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Section: Potential Cellular Location Of the Lmbd1-abcd4 Complexmentioning

confidence: 63%

mentioning

confidence: 99%

Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1

Fettelschoss

Burda

Sagné

et al. 2017

Journal of Biological Chemistry

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“…Our previous studies demonstrated that LMBD1 is localized in the lysosomal membrane [11]. In addition, LMBD1 has been found in the nucleus and in the plasma membrane [16,17]. The function of LMBD1 is not well characterized.…”

Section: Introductionmentioning

confidence: 98%

“…These interactive studies highlighted the importance of LMBD1 in lysosomal Cbl transport. An additional function for LMBD1 was recently shown by Tseng et al ., who demonstrated that knockdown of LMBRD1 is associated with an up‐regulated insulin receptor signalling cascade .…”

Section: Introductionmentioning

confidence: 99%

Lmbrd1 expression is essential for the initiation of gastrulation

Buers

Pennekamp

Nitschke

et al. 2016

J Cellular Molecular Medi

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The rare inborn cblF defect of cobalamin metabolism is caused by mutations in the limb region 1 (LMBR1) domain containing 1 gene (LMBRD1). This defect is characterized by massive accumulation of free cobalamin in lysosomes and loss of mitochondrial succinyl‐CoA synthesis and cytosolic methionine synthesis. Affected children suffer from heart defects, developmental delay and megaloblastic anemia. LMBRD1 encodes for LMBD1, a predicted lysosomal cobalamin transport protein. In this study, we determine the physiological function of LMBRD1 during embryogenesis by generating Lmbrd1 deficient mice using the Cre/LoxP system. Complete loss of Lmbrd1 function is accompanied by early embryonic death in mice. Whole mount in situ hybridization studies against bone morphogenetic protein 4 and Nodal show that initial formation of the proximal–distal axis is unaffected in early embryonic stages whereas the initiation of gastrulation is disturbed shown by the expression pattern of even skipped homeotic gene 1 and fibroblast growth factor 8 in Lmbrd1 deficient mice. We conclude that intact function of LMBD1 is essential for the initiation of gastrulation.

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“…Secreted IR truncated at the ectodomain/transmembrane junction form dimers with only a low affinity for insulin, in contrast to the full-length receptor (Chung et al, 2011). Truncation at the C-terminal end of the transmembrane region has been shown to be sufficient for the formation of high-affinity binding and negative cooperativity (Tseng et al, 2013), indicating that the C-terminal region of the ectodomain is required to facilitate the conformational changes required for high-affinity. A study reported that wild-type receptor binding characteristics were obtained with soluble insulin receptor ectodomain fusion proteins, in which the self-associating, constant domains from either immunoglobulin Fc domain were placed at the C-terminus (Bass et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Insulin receptor binding motif tagged with IgG4 Fc (Yiminsu) works as an insulin sensitizer to activate Akt signaling in hepatocytes

Wang¹,

T²,

Yang³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Insulin resistance is a key feature of obesity and type 2 diabetes mellitus (T2DM). Interaction of insulin with the insulin receptor (IR) leads to both its auto-phosphorylation and phosphorylation of tyrosine residues on the IR substrate (IRS) proteins, initiating the activation of intracellular signaling cascades. The metabolic effects of IRS are known to be mediated through pathways involving phosphatidyl-J. Wang et al. 8820©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (3): 8819-8828 (2015) inositol 3-kinase (PI-3K), which result in the activation of Akt signaling. The C-terminal region of the IR ectodomain is required to facilitate the conformational changes that are required for high-affinity binding to insulin. Furthermore, the CH2 and CH3 domains in the Fc fragments of immunoglobulins are responsible for their binding to the Fc receptor, which triggers transcytosis. In this study, we created a fusion peptide of the C-terminal end of the human IR ectodomain with the IgG4 Fc fragment, including an intervening polyG fragment to ensure enough space for insulin binding. We named this new peptide "Yiminsu", meaning an insulin sensitizer. The results of our analyses show that Yiminsu significantly facilitates insulin signaling via the activation of Akt in hepatocytes in a dose-and time-dependent manner. Further studies are required to determine whether Yiminsu can act as an insulin sensitizer.

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LMBD1 Protein Serves as a Specific Adaptor for Insulin Receptor Internalization

Cited by 32 publications

References 31 publications

Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1

Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1

Lmbrd1 expression is essential for the initiation of gastrulation

Insulin receptor binding motif tagged with IgG4 Fc (Yiminsu) works as an insulin sensitizer to activate Akt signaling in hepatocytes

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