Abstract
Synaptotagmin I (Syt I) is the calcium ion sensor for regulated release of neurotransmitter. How Syt I mediates this cellular event has been a question of extensive study for decades and yet, a clear understanding of the protein's diverse functionality has remained elusive. Using tools of thermodynamics, we have identified two intrinsic properties that may account for Syt I's functional plasticity: marginal stability and negative coupling. These two intrinsic properties have the potential to provide great conformational flexibility and suggest that Syt I's functional plasticity stems in part from subtle rearrangements in the protein's conformational ensemble. This model for Syt I function is discussed within the context of the nervous system's overall plasticity.