Fig. 8

Computational prediction of the interactions between TREM2 basic site and IL-34 negatively charged surface. (A) The complete sequence of human TREM2 showing predicted potential key residues and binding regions between residues 49–82 and 112–127 (Basic site and CDR2) for IL-34. Blue arrows denote residues predicted to be important for protein binding via PredictProtein and red arrows denote residues that increase Alzheimer’s disease risk. Residues in TREM2 immunoglobulin domain are highlighted ranging from orange to green. Residues highlighted in the darkest green had the highest number of hits and residues highlighted in the darkest orange had the lowest number of hits. Residues highlighted in grey were not screened. (B) The complete sequence of IL-34 showing predicted potential key residues and binding regions between residues 71–85, 90–100, 119–129, 142–151, and 156–179 for TREM2. Blue arrows denote residues predicted to be important for protein binding via PredictProtein. Residues highlighted in the darkest green had the highest number of hits and residues highlighted in the darkest orange had the lowest number of hits. Residues highlighted in grey were not screened. (C) Electrostatic surface potential maps showing positively charged TREM2 basic site, negatively charged IL34 surface (made up of helices 3, 4, and 5), and positively charged IL34 surface (made up of helices 1, 2, and 6). Regions with positive electrostatic surface potential are shown as blue, regions with negative electrostatic surface potential are shown as red, and neutral regions are shown as white. TREM2 is shown as grey with the basic site show as blue cartoon and the hydrophobic site shown as red cartoon. Key regions and residues for binding are labeled. IL-34 is shown as cartoon with residues making up the negatively charged surface colored in orange and residues making up the positively charged surface colored in green. The six helices are labeled. (D) Predicted complex structure of TREM2 with IL-34 shows the negatively charged surface of IL-34 (helices 3, 4, and 5) interaction with the positively charged basic site of TREM2, and key TREM2 residues identified through BLI forming hydrogen bonds and salt bridges with IL-34 residues. TREM2 is shown in gray, TREM2 basic site is shown as blue, and TREM2 hydrophobic site is shown as red. Residues making up IL-34 negatively charged surface are shown as orange and residues making up IL-34 positively charged surface are shown as green. Hydrogen bonds and salt bridges between key identified TREM2 residues from BLI and residues from IL-34 are shown as sticks and the interactions are shown as dashed yellow lines