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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).

References associated with 8.A.34 family:

Chen, Y., L. Deng, Y. Maeno-Hikichi, M. Lai, S. Chang, G. Chen, and J.F. Zhang. (2003). Formation of an endophilin-Ca2+ channel complex is critical for clathrin-mediated synaptic vesicle endocytosis. Cell. 115: 37-48. 14532001
Friesen, H., K. Colwill, K. Robertson, O. Schub, and B. Andrews. (2005). Interaction of the Saccharomyces cerevisiae cortical actin patch protein Rvs167p with proteins involved in ER to Golgi vesicle trafficking. Genetics 170: 555-568. 15802519
Guile, M.D., A. Jain, K.A. Anderson, and C.F. Clarke. (2023). New Insights on the Uptake and Trafficking of Coenzyme Q. Antioxidants (Basel) 12:. 37507930
Kirsch, K.H., M.M. Georgescu, S. Ishimaru, and H. Hanafusa. (1999). CMS: an adapter molecule involved in cytoskeletal rearrangements. Proc. Natl. Acad. Sci. USA 96: 6211-6216. 10339567
Muller, E.M., N.A. Mackin, S.E. Erdman, and K.W. Cunningham. (2003). Fig1p facilitates Ca2+ influx and cell fusion during mating of Saccharomyces cerevisiae. J. Biol. Chem. 278: 38461-38469. 12878605
Mulukala, S.K.N., S.S. Irukuvajjula, K. Kumar, K. Garai, P. Venkatesu, R. Vadrevu, and A.K. Pasupulati. (2020). Structural features and oligomeric nature of human podocin domain. Biochem Biophys Rep 23: 100774. 32617419
Ren, G., P. Vajjhala, J.S. Lee, B. Winsor, and A.L. Munn. (2006). The BAR domain proteins: molding membranes in fission, fusion, and phagy. Microbiol. Mol. Biol. Rev. 70: 37-120. 16524918
Suthar, S.K., M.M. Alam, J. Lee, J. Monga, A. Joseph, and S.Y. Lee. (2021). Bioinformatic Analyses of Canonical Pathways of TSPOAP1 and its Roles in Human Diseases. Front Mol Biosci 8: 667947. 34212002
Suzuki, H., J. Kawai, C. Taga, T. Yaoi, A. Hara, K. Hirose, Y. Hayashizaki, and S. Watanabe. (1996). Stac, a novel neuron-specific protein with cysteine-rich and SH3 domains. Biochem. Biophys. Res. Commun. 229: 902-909. 8954993
Takahashi, Y., N. Tsotakos, Y. Liu, M.M. Young, J. Serfass, Z. Tang, T. Abraham, and H.G. Wang. (2016). The Bif-1-Dynamin 2 membrane fission machinery regulates Atg9-containing vesicle generation at the Rab11-positive reservoirs. Oncotarget 7: 20855-20868. 26980706
Wong King Yuen, S.M., M. Campiglio, C.C. Tung, B.E. Flucher, and F. Van Petegem. (2017). Structural insights into binding of STAC proteins to voltage-gated calcium channels. Proc. Natl. Acad. Sci. USA 114: E9520-E9528. 29078335