JAK2 dimerization mechanism. (A) The computational model of the FL hMPL-hTPO-JAK2 complex embedded in a lipid bilayer membrane. Left: the modeling construct before MD simulations; right: the system after a 1.3-μs MD simulation; bottom: JAK2 domain scheme with each domain color coded. (B) Interaction between the JAK2 FERM domain (red) and hMPL Box1 domain (gray). (C) Interaction between the JAK2 SH2 domain (yellow) and hMPL Box2 domain (gray). (D) JAK2 dimerization via trans PK-PK interaction. Top: stability analysis of the PK-PK (green) interface in the presence of hTPO, determined by measuring the distance between the center of mass of Cα atoms within residues (530-540 and 545-808) across both JAK2 PK domains. The bottom panel provides a detailed view of the intermolecular interactions between 2 PK domains in the FL WT hMPL-hTPO-JAK2 system. (E) JAK2 V617F constitutive activity mechanism. Top: detailed intermolecular view of the PK-PK interface with V617F mutation within the apo hMPL-JAK2 structure. Bottom: stability analysis of apo hMPL PK-PK interface. The introduction of F617 leads to the formation of π-π stacking interactions. All key residues are highlighted as sticks.