9.B.17 The VAMP-associated protein (VAP) Family

The VAMP-associated proteins (VAPs) are highly conserved integral endoplasmic reticulum membrane proteins implicated in diverse cellular functions, including the regulation of lipid transport and homeostasis, membrane trafficking, neurotransmitter release, stabilization of presynaptic microtubules, and the unfolded protein response. A single missense mutation within the human VAP-B gene was identified in three forms of familial motor neuron disease. Yeast, flies and mammals have VAPs. There is a network of VAP-interacting proteins. Their mechanisms of action are not well understood (Lev et al., 2008). However, VAPs form a network with a reticulophagy receptor and Atg8 (Yang and Klionsky 2020).

The endoplasmic reticulum transmembrane protein vesicle-associated membrane protein-associated protein (VAP) plays a central role in the formation and function of membrane contact sites (MCS) through its interactions with proteins. The major sperm protein (MSP) domain of VAP binds to a variety of sequences which are referred to as FFAT-like motifs. Furuita et al. 2021 investigated the interactions of eight peptides containing FFAT-like motifs with the VAP-A MSP domain (VAP-AMSP ) by solution NMR. Six of eight peptides were specifically bound to VAP-A. The RNA-dependent RNA polymerase of severe acute respiratory syndrome coronavirus 2 has an FFAT-like motif which specifically binds to VAP-AMSP as well as other FFAT-like motifs. TMED family proteins (TMED1 - 10) are found in 4 subgroups, alpha, beta, gamma and delta, and their roles in human diseases have been reviewed (Zhou et al. 2023).