Intramembrane cleavage of TREM2 is determined by its intrinsic structural dynamics

Abstract

words, 1027 characters)Sequence variants of the microglial expressed TREM2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease. TREM2 requires a stable interaction with DAP12 in the membrane to initiate signaling, which is terminated by TREM2 ectodomain shedding and subsequent intramembrane cleavage by g-secretase. To understand the structural basis for the specificity of the intramembrane cleavage event, we determined the solution structure of the TREM2 transmembrane helix (TMH). Due to the presence of a charged amino acid in the membrane region the TREM2-TMH adopts a kinked structure with increased flexibility. Charge removal leads to TMH stabilization and reduced dynamics, similar to its structure in complex with DAP12. Strikingly, these dynamical features perfectly correlate with the site of the initial g-secretase cleavage event. These data suggest an unprecedented cleavage mechanism by g-secretase where flexible TMH regions are identified to initiate substrate cleavage.Single transmembrane helices remain a major challenge for structure determination approaches since they are highly flexible and therefore not suitable for crystallization. Solution NMR offers the advantage to study these dynamic domains in different membrane mimetics in solution and to obtain