Biology subjects

Shepard, J.

Publications and source records attributed to Shepard, J..

2 recordsLinked to original sources

bioRxiv2023

The crystal and cryo-EM structures of PLCγ2 reveal dynamic inter-domain recognitions in autoinhibition

Abstract/SummaryPhospholipase C gamma 2 (PLC{gamma}2) plays important roles in cell signaling downstream of various membrane receptors. PLC{gamma}2 contains a multi-domain inhibitory region critical for its regulation, while it has remained unclear how these domains contribute to PLC{gamma}2 activity modulation. Here we determined three structures of human PLC{gamma}2 in autoinhibited states, which reveal dynamic interactions at the autoinhibition interface, involving the conformational flexibility of the SH3 domain in the inhibitory region, and its previously unknown interaction with a C-terminal helical domain in the core region. We also determined a structure of PLC{gamma}2 bound to the kinase domain of fibroblast growth factor receptor 1 (FGFR1), which demonstrates the recognition of FGFR1 by the nSH2 domain in the inhibitory region of PLC{gamma}2. Our results provide new structural insights into PLC{gamma}2 regulation that will facilitate future mechanistic studies to understand the entire activation process.

biochemistry↗

bioRxiv2020

High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

In both sickle cell disease (SCD) and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. Extravascular haemolysis in SCD correlates with high mannose glycan levels on RBCs. Infection of RBCs with Plasmodium falciparum expose surface mannose N-glycans on healthy RBCs, which occurred at significantly higher levels on RBCs from subjects with sickle cell trait compared to those lacking haemoglobin S. The glycans were associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans, a novel response to cellular stress, is the first molecular mechanism common to both the pathogenesis of SCD and resistance to severe malaria in sickle cell trait.

immunology↗