Sequence variants of the microglial expressedTREM2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease.TREM2 requires a stable interaction withDAP12 in the membrane to initiate signaling, which is terminated byTREM2 ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase. To understand the structural basis for the specificity of the intramembrane cleavage event, we determined the solution structure of theTREM2 transmembrane helix (TMH). Caused by the presence of a charged amino acid in the membrane region, theTREM2-TMHadopts a kinked structure with increased flexibility. Charge removal leads toTMHstabilization and reduced dynamics, similar to its structure in complex withDAP12. Strikingly, these dynamical features match with the site of the initial gamma-secretase cleavage event. These data suggest an unprecedented cleavage mechanism by gamma-secretase where flexibleTMHregions act as key determinants of substrate cleavage specificity.