1.F.3.  The EH Domain-containing Protein 1 (ETMP1) Family 

ETMP1 is an ATP- and membrane-binding protein that controls membrane reorganization and tubulation upon ATP hydrolysis. In vitro, it causes vesiculation of endocytic membranes (Cai et al. 2013). It acts in early endocytic membrane fusion and membrane trafficking of recycling endosomes (Rahajeng et al. 2010). Lipid and ion transport, mitosome fission, and quality control are potential processes that are mediated by the ETMP1-EHD1-tethered mitosome-endosome contact site in E. histolytica (Santos et al. 2022).

 


 

References:

Cai, B., S.S.P. Giridharan, J. Zhang, S. Saxena, K. Bahl, J.A. Schmidt, P.L. Sorgen, W. Guo, N. Naslavsky, and S. Caplan. (2013). Differential roles of C-terminal Eps15 homology domain proteins as vesiculators and tubulators of recycling endosomes. J. Biol. Chem. 288: 30172-30180.
Della Sala, A., L. Tasca, C. Butnarasu, V. Sala, G. Prono, A. Murabito, O.V. Garbero, E. Millo, L. Terranova, F. Blasi, A. Gramegna, S. Aliberti, A. Massarotti, S. Visentin, E. Hirsch, and A. Ghigo. (2024). A nonnatural peptide targeting the A-kinase anchoring function of PI3Kγ for therapeutic cAMP modulation in pulmonary cells. J. Biol. Chem. 300: 107873.
Rahajeng, J., S.S. Giridharan, N. Naslavsky, and S. Caplan. (2010). Collapsin response mediator protein-2 (Crmp2) regulates trafficking by linking endocytic regulatory proteins to dynein motors. J. Biol. Chem. 285: 31918-31922.
Santos, H.J., Y. Hanadate, K. Imai, H. Watanabe, and T. Nozaki. (2022). Entamoeba histolytica EHD1 Is Involved in Mitosome-Endosome Contact. mBio 13: e0384921.
Zhang, Y., X. Yang, Y. Liu, L. Ge, J. Wang, X. Sun, B. Wu, and J. Wang. (2022). Vav2 is a novel APP-interacting protein that regulates APP protein level. Sci Rep 12: 12752.
Examples:

TC#NameOrganismal TypeExample
1.F.3.1.1

EHD1 of 534 aas and 0 TMSs.

EHD1 of Homo sapiens

 
1.F.3.1.2

Intersectin-1 isoform X4 of 1631 aa

Intersectin 1 of Dendroctonus ponderosae (mountain pine beetle)

 
1.F.3.1.3

Intersectin-1-like isoform X2 of 1738 aas.

Intersectin-1 of Scleropages formosus (Asian bonytongue)

 
1.F.3.1.4

Guanine nucleotide exchange factor, VAV2, of 878 aas and possibly 3 TMSs in a 1 (N-terminus) + 2 TMSs (residues 220 - 280). VAV2 is a factor for the Rho family of Ras-related GTPases. It plays a role in angiogenesis. Its recruitment by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly.  Vav2 is also an amyloid precursor protein (APP)-interacting protein that regulates APP protein levels (Zhang et al. 2022). APP has TC# 1.C.50.1.2.

VAV2 of Homo sapiens

 
1.F.3.1.5

Miltosome-endosome contact site proteins, EHD1 (EHI105270; uniprot C4M131) of 507 aas and 0 TMSs, and ETMP1 (EHI175060; uniprot C4LZN1) of 256 aas and 1 or 2 TMSs at the C-terminus and possibly at about residue 80.  Membrane contact sites (MCSs) are key regulators of interorganellar communication and have been widely demonstrated between various organelles, but studies on MCSs involving mitochondrion-related organelles (MROs), present in some anaerobic parasitic protozoans, remain scarce. Entamoeba histolytica, the etiological agent of amoebiasis, possesses an MRO called the mitosome. This organelle is crucial for cellular differentiation and disease transmission, thereby contributing to the amoeba's parasitic lifestyle. The interaction between the Entamoeba-specific transmembrane mitosomal protein (ETMP1) and EH domain-containing protein (EHD1) showcases a mitosome-endosome contact site in E. histolytica (Santos et al. 2022). Despite their  divergent and reduced nature, MROs like mitosomes conserve mechanisms for interorganellar cross talk. Santos et al. 2022 suggested that lipid and ion transport, mitosome fission, and quality control are potential processes that are mediated by the ETMP1-EHD1-tethered mitosome-endosome contact site in E. histolytica.

Mitosome-endosome contact site of Entamoeba histolytica

 
1.F.3.1.6

A-Protein kinase ancoring protein of 2817 aas with 0 TMSs. Similarity of the sequence of this protein with other members of this family occur only at the C-terminus of the protein.  A-kinase anchoring proteins (AKAPs) are key orchestrators of cAMP signaling that act by recruiting protein kinase A (PKA) in proximity of its substrates and regulators to specific subcellular compartments. Modulation of AKAPs function offers the opportunity to achieve compartment-restricted modulation of the cAMP/PKA axis, paving the way to new targeted treatments. For instance, blocking the AKAP activity of phosphoinositide 3-kinase γ (PI3Kγ) improves lung function by inducing cAMP-mediated bronchorelaxation, ion transport, and antiinflammatory responses. Here, we report the generation of a nonnatural peptide, D-retroinverso (DRI)-Pep #20, optimized to disrupt the AKAP function of PI3Kγ. DRI-Pep #20 mimicked the native interaction between the N-terminal domain of PI3Kγ and PKA, demonstrating nanomolar affinity for PKA, high resistance to protease degradation and high permeability to the pulmonary mucus barrier (Della Sala et al. 2024).

Anchoring Protein Kinase A of Homo sapiens