Reciprocal Unlocking Between Autoinhibitory CaMKII and Tiam1: A Simulation Study

Ca²⁺/Calmodulin-activated kinase II (CaMKII) as a switchable enzyme with autonomous inhibition is critical to learning and memory, working together with its various regulators, such as Tiam1 (T-cell lymphoma invasion and metastasis 1), a guanine nucleotide exchange factor (GEF). We here propose a model of molecular memory that both CaMKII and Tiam1 would be concurrently switched between the two basic states: autonomously-inhibited versus reciprocally-unlocked, by their multi-domain interactions. It is reported that the kinase domain (KD) of CaMKII interacts with Tiam1 mainly through the carboxyl tail (CT). Based on the documented evidence and our simulation results, we propose that CT could bind the GEF domain DH–PHC thus playing a key role in Tiam1 autoinhibition, which is relieved by CT/KD binding. This implies a duo complex of CaMKII/Tiam1 that consists of two binding pairs: DH–PHC/AID in addition to CT/KD, providing new mechanistic insights for both CaMKII and Tiam1. Taken together, cellular activities would be concurrently memorized by reciprocal interactions into both CaMKII and Tiam1, potentially more robust and reliable, awaiting future experimental explorations.