Membrane Curvature Protein Exhibits Interdomain Flexibility and Binds a Small GTPase

King, G. J.; Stöckli, Jacqueline; Hu, Shuhong; Winnen, Brit; Duprez, Wilko; Meoli, Christopher C.; Junutula, Jagath R.; Jarrott, Russell; James, David E.; Whitten, Andrew E.; Martin, Jennifer L.

doi:10.1074/jbc.m112.349803

Cited by 18 publications

(28 citation statements)

References 48 publications

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“…This concurred with the binding of APPL2 to Rab31 found previously by yeast two-hybrid screening (King et al ., 2012). Both studies also show that APPL2 has a preference for binding to Rab31 over Rab5a.…”

Section: Discussionsupporting

confidence: 92%

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Rab31 and APPL2 enhance FcγR-mediated phagocytosis through PI3K/Akt signaling in macrophages

Yeo

Wall

Luo

et al. 2015

MBoC

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Section: Discussionsupporting

confidence: 92%

“…A yeast two-hybrid study showed that Rab31 preferentially binds to the complementary adaptor APPL2 (King et al ., 2012), although, to our knowledge, APPL2 has not previously been examined in phagocytosis or in macrophages.…”

Section: Resultsmentioning

confidence: 99%

Rab31 and APPL2 enhance FcγR-mediated phagocytosis through PI3K/Akt signaling in macrophages

Yeo

Wall

Luo

et al. 2015

MBoC

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“…The final refined model contains 364 residues (a.a. 1–364) for one monomer and 361 residues (a.a. 1–361) for the other. The BAR domains within the dimer form a bundle that contains eight-helices, which is similar to the BAR domains of APPL1 and APPL2 (King et al, 2012; Li et al, 2007a; Zhu et al, 2007), but different from other reported BAR domains (Gallop et al, 2006; Peter et al, 2004; Pykäläinen et al, 2011; Shimada et al, 2007). The dimer interface has a large area (4100 Å 2 ), and contains mainly hydrophobic residues that likely mediate dimerization.…”

Section: Resultsmentioning

confidence: 65%

A PH Domain in ACAP1 Possesses Key Features of the BAR Domain in Promoting Membrane Curvature

et al. 2014

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SUMMARY The BAR (Bin-Amphiphysin-Rvs) domain undergoes dimerization to produce a curved protein structure, which superimposes onto membrane through electrostatic interactions to sense and impart membrane curvature. In some cases, a BAR domain also possesses an amphipathic helix that inserts into the membrane to induce curvature. ACAP1 (Arfgap with Coil coil, Ankyrin repeat and PH domain protein 1) contains a BAR domain. Here, we show that this BAR domain can neither bind membrane nor impart curvature, but instead, requires a neighboring PH (Pleckstrin Homology) domain to achieve these functions. Specific residues within the PH domain are responsible for both membrane binding and curvature generation. The BAR domain adjacent to the PH domain instead interacts with the BAR domains of neighboring ACAP1 proteins to enable clustering at the membrane. Thus, we have uncovered the molecular basis for an unexpected and unconventional collaboration between PH and BAR domains in membrane bending.

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“…Therefore, the opposite effects of APPL1 and APPL2 on insulin-stimulated glucose uptake are attributed to the differential binding of these two adaptor proteins to Akt and TBC1D1. In line with these findings, APPL1 and APPL2 have been shown to bind to various types of Rab-GTPases involved in membrane trafficking (17,19). The binding of APPL1 and APPL2 to various sets of intracellular signaling molecules may be due to their differences in oligomerization, surface charges, and/or subcellular localization (17,18,31,32).…”

Section: Discussionmentioning

confidence: 61%

“…On the other hand, an in vitro study demonstrated that these two proteins possess distinct or even opposite functions in regulating glucose and lipid metabolism (16). Structural analysis revealed that APPL2 incorporates two homodimers, whereas APPL1 incorporates only one homodimer in the asymmetric unit (17)(18)(19). Although APPL1 binds to the adiponectin receptors and increases adiponectin-induced glucose uptake and fatty acid oxidation, APPL2 inhibits adiponectin actions in muscle cells (13,16).…”

mentioning

confidence: 99%

The Adaptor Protein APPL2 Inhibits Insulin-Stimulated Glucose Uptake by Interacting With TBC1D1 in Skeletal Muscle

et al. 2014

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Insulin stimulates glucose uptake by promoting the trafficking of GLUT4 to the plasma membrane in muscle cells, and impairment of this insulin action contributes to hyperglycemia in type 2 diabetes. The adaptor protein APPL1 potentiates insulin-stimulated Akt activation and downstream actions. However, the physiological functions of APPL2, a close homolog of APPL1, in regulating glucose metabolism remain elusive. We show that insulin-evoked plasma membrane recruitment of GLUT4 and glucose uptake are impaired by APPL2 overexpression but enhanced by APPL2 knockdown. Likewise, conditional deletion of APPL2 in skeletal muscles enhances insulin sensitivity, leading to an improvement in glucose tolerance. We identified the Rab-GTPaseactivating protein TBC1D1 as an interacting partner of APPL2. Insulin stimulates TBC1D1 phosphorylation on serine 235, leading to enhanced interaction with the BAR domain of APPL2, which in turn suppresses insulinevoked TBC1D1 phosphorylation on threonine 596 in cultured myotubes and skeletal muscle. Substitution of serine 235 with alanine diminishes APPL2-mediated inhibition on insulin-dependent TBC1D1 phosphorylation on threonine 596 and the suppressive effects of TBC1D1 on insulin-induced glucose uptake and GLUT4 translocation to the plasma membrane in cultured myotubes. Therefore, the APPL2-TBC1D1 interaction is a key step to fine tune insulin-stimulated glucose uptake by regulating the membrane recruitment of GLUT4 in skeletal muscle.

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Membrane Curvature Protein Exhibits Interdomain Flexibility and Binds a Small GTPase

Cited by 18 publications

References 48 publications

Rab31 and APPL2 enhance FcγR-mediated phagocytosis through PI3K/Akt signaling in macrophages

Rab31 and APPL2 enhance FcγR-mediated phagocytosis through PI3K/Akt signaling in macrophages

A PH Domain in ACAP1 Possesses Key Features of the BAR Domain in Promoting Membrane Curvature

The Adaptor Protein APPL2 Inhibits Insulin-Stimulated Glucose Uptake by Interacting With TBC1D1 in Skeletal Muscle

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