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.
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December 2020
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The cover image shows the ternary complex structure of pol? incorporating dCTP* opposite templating xanthine. In this issue Jung and colleagues (pp. 4797–4810) demonstrate the solved structure of human DNA polymerase η (ploη) catalyzing across xanthine and hypoxanthine. Image courtesy of Seongmin Lee.
Research Article|
December 24 2020
Crystal structure of human APPL BAR-PH heterodimer reveals a flexible dimeric BAR curve: implication in mutual regulation of endosomal targeting
Yujie Chen;
Yujie Chen
*
Data curation, Formal analysis, Investigation, Visualization, Writing - original draft
1School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
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Wen Zhang;
Wen Zhang
*
Data curation, Formal analysis, Validation, Investigation, Visualization, Writing - original draft, Writing - review & editing
1School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
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Bin Chen;
Bin Chen
*
Data curation, Formal analysis, Investigation
2Department of Medicine, The University of Hong Kong, Hong Kong, China
3Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
4State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
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Ying Liu;
Ying Liu
Data curation, Formal analysis, Investigation
5Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China
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Yuhui Dong;
Yuhui Dong
Resources, Supervision
5Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China
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Aimin Xu;
2Department of Medicine, The University of Hong Kong, Hong Kong, China
3Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
4State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
Correspondence: Quan Hao(qhao@hku.hk) or Aimin Xu (amxu@hkucc.hku.hk)
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Quan Hao
Conceptualization, Resources, Supervision, Funding acquisition, Validation, Investigation, Writing - original draft, Project administration, Writing - review & editing
1School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
Correspondence: Quan Hao(qhao@hku.hk) or Aimin Xu (amxu@hkucc.hku.hk)
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Publisher: Portland Press Ltd
Received:
May 26 2020
Revision Received:
November 26 2020
Accepted:
November 30 2020
Accepted Manuscript online:
December 01 2020
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2020
Biochem J (2020) 477 (24): 4769–4783.
Article history
Received:
May 26 2020
Revision Received:
November 26 2020
Accepted:
November 30 2020
Accepted Manuscript online:
December 01 2020
Citation
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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