The APPL (adaptor proteins containing pleckstrin homology domain, phosphotyrosine binding domain and a leucine zipper motif) family consists of two isoforms, APPL1 and APPL2. By binding to curved plasma membrane, these adaptor proteins associate with multiple transmembrane receptors and recruit various downstream signaling components. They are involved in the regulation of signaling pathways evoked by a variety of extracellular stimuli, such as adiponectin, insulin, FSH (follicle stimulating hormone), EGF (epidermal growth factor). And they play important roles in cell proliferation, apoptosis, glucose uptake, insulin secretion and sensitivity. However, emerging evidence suggests that APPL1 and APPL2 perform different or even opposite functions and the underlying mechanism remains unclear. As APPL proteins can either homodimerize or heterodimerize in vivo, we hypothesized that heterodimerization of APPL proteins might account for the mechanism. By solving the crystal structure of APPL1–APPL2 BAR-PH heterodimer, we find that the overall structure is crescent-shaped with a longer curvature radius of 76 Å, compared with 55 Å of the APPL1 BAR-PH homodimer. However, there is no significant difference of the curvature between APPL BAR-PH heterodimer and APPL2 homodimer. The data suggest that the APPL1 BAR-PH homodimer, APPL2 BAR-PH homodimer and APPL1/APPL2 BAR-PH heterodimer may bind to endosomes of different sizes. Different positive charge distribution is observed on the concave surface of APPL BAR-PH heterodimer than the homodimers, which may change the affinity of membrane association and subcellular localization. Collectively, APPL2 may regulate APPL1 function through altering the preference of endosome binding by heterodimerization.
Crystal structure of human APPL BAR-PH heterodimer reveals a flexible dimeric BAR curve: implication in mutual regulation of endosomal targeting
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Yujie Chen, Wen Zhang, Bin Chen, Ying Liu, Yuhui Dong, Aimin Xu, Quan Hao; Crystal structure of human APPL BAR-PH heterodimer reveals a flexible dimeric BAR curve: implication in mutual regulation of endosomal targeting. Biochem J 23 December 2020; 477 (24): 4769–4783. doi: https://doi.org/10.1042/BCJ20200438
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