Emerging Functional Differences between the Synaptotagmin and Ferlin Calcium Sensor Families

Abstract

The ferlin family proteins have emerged as multi-C2 domain regulators of calcium-triggered membrane fusion and fission events. While initially determined to share many of the features of members of the synaptotagmin family of calcium sensors, ferlins in more recent studies have been found to interact directly with non-neuronal voltage-gated calcium channels and nucleate the assembly of membrane-trafficking protein complexes, functions that distinguish them from the more well studied members of the synaptotagmin family. Here we highlight some of the recent findings that have advanced our understanding of ferlins and their functional differences with the synaptotagmin family.

Figure 1

Domain organization for proteins with multiple C2 domains. Structurally, all members of the ferlin family have a single-pass transmembrane domain at the C-terminus (thin rectangle) and between four and seven C2 domains (ovals, denoted C2A–C2F), as shown for representative ferlins otoferlin and dysferlin. A predicted coiled coil domain (cylinder) and dysF domain (thick rectangle) reside between C2C and C2D. The boxed region shows the predicted organization for other proteins with multiple C2 domains. Members of the synaptotagmin family have a single-pass transmembrane domain at the N-terminus (thin rectangle) and two C2 domains (ovals, denoted C2A and C2B). The inset shows the structure of otoferlin C2A (Protein Data Bank entry 3L9B).

Figure 2

Contribution of otoferlin and dysferlin to the vesicle cycle and associated binding partners. Three stages of the vesicle cycle are depicted, with binding partners for otoferlin (green) and dysferlin (red) depicted for each stage. Vesicle docking/priming (stage 1) via otoferlin and dysferlin may be partly mediated by PIP2 lipids residing at the cell membrane. Ferlin-mediated membrane fusion (stage 2) is regulated by the influx of calcium through Cav1.1 or Cav1.3 channels and is associated with a variety of additional proteins that form an exocytotic complex. Postfusion (stage 3), otoferlin is endocytosed via an adaptor protein 2 (AP2) pathway, while interaction of dysferlin with caveolin-3 influences retention or endocytosis from the membrane.