scholarly journals Marked structural rearrangement of mannose 6-phosphate/IGF2 receptor at different pH environments

2020 ◽  
Vol 6 (7) ◽  
pp. eaaz1466 ◽  
Author(s):  
Rong Wang ◽  
Xiaofeng Qi ◽  
Philip Schmiege ◽  
Elias Coutavas ◽  
Xiaochun Li
Keyword(s):  
Cell Surface ◽  
Structural Rearrangement ◽  
Repeated Sequences ◽  
Structural Basis ◽  
Acidic Ph ◽  
Surface Receptors ◽  
Ligand Dissociation ◽  
Ph Dependent ◽  
Endocytic Compartments ◽  
Dissociated State

Many cell surface receptors internalize their ligands and deliver them to endosomes, where the acidic pH causes the ligand to dissociate. The liberated receptor returns to the cell surface in a process called receptor cycling. The structural basis for pH-dependent ligand dissociation is not well understood. In some receptors, the ligand binding domain is composed of multiple repeated sequences. The insulin-like growth factor 2 receptor (IGF2R) contains 15 β strand–rich repeat domains. The overall structure and the mechanism by which IGF2R binds IGF2 and releases it are unknown. We used cryo-EM to determine the structures of the IGF2R at pH 7.4 with IGF2 bound and at pH 4.5 in the ligand-dissociated state. The results reveal different arrangements of the receptor in different pH environments mediated by changes in the interactions between the repeated sequences. These results have implications for our understanding of ligand release from receptors in endocytic compartments.

scholarly journals Structural basis for activation and non-canonical catalysis of the Rap GTPase activating protein domain of plexin

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Yuxiao Wang ◽  
Heath G Pascoe ◽  
Chad A Brautigam ◽  
Huawei He ◽  
Xuewu Zhang
Keyword(s):  
Cell Surface ◽  
Axon Guidance ◽  
Active Site ◽  
Large Scale ◽  
Catalytic Mechanism ◽  
Protein Domain ◽  
Structural Basis ◽  
Gtpase Activating Protein ◽  
Gtp Hydrolysis ◽  
Surface Receptors

Plexins are cell surface receptors that bind semaphorins and transduce signals for regulating neuronal axon guidance and other processes. Plexin signaling depends on their cytoplasmic GTPase activating protein (GAP) domain, which specifically inactivates the Ras homolog Rap through an ill-defined non-canonical catalytic mechanism. The plexin GAP is activated by semaphorin-induced dimerization, the structural basis for which remained unknown. Here we present the crystal structures of the active dimer of zebrafish PlexinC1 cytoplasmic region in the apo state and in complex with Rap. The structures show that the dimerization induces a large-scale conformational change in plexin, which opens the GAP active site to allow Rap binding. Plexin stabilizes the switch II region of Rap in an unprecedented conformation, bringing Gln63 in Rap into the active site for catalyzing GTP hydrolysis. The structures also explain the unique Rap-specificity of plexins. Mutational analyses support that these mechanisms underlie plexin activation and signaling.

scholarly journals Kinetic proofreading of lipochitooligosaccharides determines signal activation of symbiotic plant receptors

2021 ◽  
Vol 118 (44) ◽  
pp. e2111031118
Author(s):  
Kira Gysel ◽  
Mette Laursen ◽  
Mikkel B. Thygesen ◽  
Damiano Lironi ◽  
Zoltán Bozsóki ◽  
...  
Keyword(s):  
Cell Surface ◽  
Binding Site ◽  
Receptor Activation ◽  
Cell Surface Receptor ◽  
Structural Basis ◽  
Environmental Signals ◽  
Surface Receptors ◽  
Ligand Selectivity ◽  
Hydrophobic Patch ◽  
Kinetic Proofreading

Plants and animals use cell surface receptors to sense and interpret environmental signals. In legume symbiosis with nitrogen-fixing bacteria, the specific recognition of bacterial lipochitooligosaccharide (LCO) signals by single-pass transmembrane receptor kinases determines compatibility. Here, we determine the structural basis for LCO perception from the crystal structures of two lysin motif receptor ectodomains and identify a hydrophobic patch in the binding site essential for LCO recognition and symbiotic function. We show that the receptor monitors the composition of the amphiphilic LCO molecules and uses kinetic proofreading to control receptor activation and signaling specificity. We demonstrate engineering of the LCO binding site to fine-tune ligand selectivity and correct binding kinetics required for activation of symbiotic signaling in plants. Finally, the hydrophobic patch is found to be a conserved structural signature in this class of LCO receptors across legumes that can be used for in silico predictions. Our results provide insights into the mechanism of cell-surface receptor activation by kinetic proofreading of ligands and highlight the potential in receptor engineering to capture benefits in plant–microbe interactions.

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