8.A.34 The Endophilin (Endophilin) Family
Endophilins A1 and A2 play a role in synaptic vesicle endocytosis in mammals which is regulated by Ca2+ influx into neurons (Ren et al., 2006). Both endophilin A1 and A2 exhibit direct binding to voltage-gated Ca2+ channels (VGCCs). This interaction is regulated by Ca2+ binding to a site in the central domain of endophilins A1 and A2. The endophilin A1 and A2 SH3 domains interact with a proline-rich motif in the central domain adjacent to the Ca2+-binding site. Ca2+ binding to the central domain of endophilins A1 and A2 breaks this intramolecular SH3 interaction and allows interaction of the central domain with VGCCs. Endophilin A2 association with VGCCs is important in vivo since transient expression in hippocampal neurons of a mutant endophilin A2 construct that constitutively binds VGCCs inhibits endocytosis (possibly by preventing Ca2+ influx) (Chen et al., 2003). This regulation of Ca2+ influx is somewhat reminiscent of the role of Rvs161p in low-affinity Ca2+ influx (TC# 9.A.46) during mating in yeast (Muller et al., 2003).
Excitation-contraction (EC) coupling in skeletal muscle requires functional and mechanical coupling between L-type voltage-gated calcium channels (CaV1.1) and the ryanodine receptor (RyR1). STAC3 is an essential protein for EC coupling and is part of a group of three proteins that can bind and modulate L-type voltage-gated calcium channels. Wong King Yuen et al. 2017 reporte crystal structures of tandem-SH3 domains of different STAC isoforms up to 1.2-A resolution. These form a rigid interaction through a conserved interdomain interface. They identified linker connecting transmembrane repeats II and III in two different CaV isoforms as a binding site for the SH3 domains and reported a crystal structure of the complex with the STAC2 isoform. The interaction site includes the location for a disease variant in STAC3 that has been linked to Native American myopathy (NAM). Introducing the mutation does not cause misfolding of the SH3 domains, but abolishes the interaction. Disruption of the interaction via mutations in the II-III loop perturbs skeletal muscle EC coupling, but preserves the ability of STAC3 to slow down inactivation of CaV1.2 (Wong King Yuen et al. 2017).
The neuronal regulatory Src homology 3 (SH3) and cysteine-rich domain-containing protein, STAC, of 402 aas and 0 TMSs (Suzuki et al. 1996).
STAC of Homo sapiens
SH3 and cysteine-rich domain-containing protein 3, STAC3 of 364 aas. Excitation-contraction (EC) coupling in skeletal muscle requires functional and mechanical coupling between L-type voltage-gated calcium channels (CaV1.1) and the ryanodine receptor (RyR1), and STAC3 is an essential protein for EC coupling. It is part of a group of three proteins that can bind and modulate L-type voltage-gated calcium channels (Wong King Yuen et al. 2017).
STAC3 of Homo sapiens
Endophilin-B1 of 365 aas; also called Bif-1. Acts with dynamin 2 (DNM2; P50570; similar to 9.A.63.1.1) to cause membrane fission of vesicles/tubular structures containing the Atg9 protein of 839 aas and 6 - 8 TMSs (9.a.15.2.1; Takahashi et al. 2016).
Endophilin-B1 of Homo sapiens