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. 



This family belongs to the Vesicle-associated Membrane Protein (VAMP) Superfamily.

 

References:

Furuita, K., M. Hiraoka, K. Hanada, T. Fujiwara, and C. Kojima. (2021). Sequence requirements of the FFAT-like motif for specific binding to VAP-A are revealed by NMR. FEBS Lett. 595: 2248-2256.

Lev, S., D. Ben Halevy, D. Peretti, and N. Dahan. (2008). The VAP protein family: from cellular functions to motor neuron disease. Trends Cell Biol. 18: 282-290.

Li, M.T., W. Di, H. Xu, Y.K. Yang, H.W. Chen, F.X. Zhang, Z.H. Zhai, and D.Y. Chen. (2013). Negative regulation of RIG-I-mediated innate antiviral signaling by SEC14L1. J. Virol. 87: 10037-10046.

Mei, S., J. Lin, Z. Liu, and C. Li. (2022). A Novel Mutation in the FYCO1 Gene Causing Congenital Cataract: Case Study of a Chinese Family. Dis Markers 2022: 5838104.

Mendes, L.F.S. and A.J. Costa-Filho. (2022). A gold revision of the Golgi Dynamics (GOLD) domain structure and associated cell functionalities. FEBS Lett. 596: 973-990.

Ribeiro, F.M., L.T. Ferreira, S. Marion, S. Fontes, M. Gomez, S.S. Ferguson, M.A. Prado, and V.F. Prado. (2007). SEC14-like protein 1 interacts with cholinergic transporters. Neurochem Int 50: 356-364.

Sohda, M., Y. Misumi, A. Yamamoto, A. Yano, N. Nakamura, and Y. Ikehara. (2001). Identification and characterization of a novel Golgi protein, GCP60, that interacts with the integral membrane protein giantin. J. Biol. Chem. 276: 45298-45306.

Yamanaka, T., R. Nishiyama, T. Shimogori, and N. Nukina. (2020). Proteomics-Based Approach Identifies Altered ER Domain Properties by ALS-Linked VAPB Mutation. Sci Rep 10: 7610.

Yang, Y. and D.J. Klionsky. (2020). A novel reticulophagy receptor, Epr1: a bridge between the phagophore protein Atg8 and ER transmembrane VAP proteins. Autophagy 1-2. [Epub: Ahead of Print]

Examples:

TC#NameOrganismal TypeExample
9.B.17.1.1

Vesicle-associated membrane protein-associated protein-B/C, VAMP-B/C or VAPB). It has 243aas with has one C-terminal TMS with the large N-terminal domain extracellular. It binds to several organelle-resident membrane proteins to mediate ER-organelle tethering. Mutations give rise toamyotrophic lateral sclerosis (ALS) because the mutant proteins induce protein misfolding and aggregation, leading to ER disorganization. Thus, altered ER domain properties and impaired ER-organelle tethering result (Yamanaka et al. 2020).

Animals

VAPB of Homo sapiens (O95292)

 
9.B.17.1.2

Plant VAMP (vesicle-associated membrane protein) family protein of 220 aas and one C-terminal TMS.

VAMP of Arabidopsis thaliana

 
9.B.17.1.3

Motile sperm domain-containing protein 2, MSDP2, of 523 aas and one C-terminal TMS.

MSDP2 of Cyprinodon tularosa

 
9.B.17.1.4

MSP (Major sperm protein) domain protein of 224 aas and 1 or 2 TMSs.

MSP protein of Theileria parva strain Muguga

 
9.B.17.1.5

Uncharacterized protein of 216 aas and 1 TMS

UP of Trypanosoma brucei gambiense

 
9.B.17.1.6

Uncharacterized protein of 392 aas and 1 (C-terminal) or 2 (N-terminal) TMSs

UP of Jimgerdemannia flammicorona

 
9.B.17.1.7

Vesicle-associated protein 4-2-like of 267aas and possibly 1 or 2 TM

VAP of Gossypium hirsutum (Upland cotton) (Gossypium mexicanum)

 
Examples:

TC#NameOrganismal TypeExample
9.B.17.2.1

Sec14-like protein1, Sec14L1 of 715 aas and 0 TMSs. It may play a role in innate immunity by inhibiting the antiviral RIG-I signaling pathway. In this pathway, it functions as a negative regulator of DDX58/RIG-I, the cytoplasmic sensor of viral nucleic acids. It prevents the interaction of DDX58 with MAVS/IPS1, an important step in signal propagation (Li et al. 2013). It may also regulate the SLC18A3 and SLC5A7 cholinergic transporters (Ribeiro et al. 2007). It contains a Golgi Dynamics (GOLD) domain (Mendes and Costa-Filho 2022).

Sec14L1 of Homo sapiens

 
9.B.17.2.2

Sec14L4 of 406 aas and 0 TMSs. It is a probable hydrophobic ligand-binding protein that may play a role in the transport of hydrophobic ligands like tocopherol, squalene and phospholipids.

Sec14L4 of Homo sapiens

 
9.B.17.2.3

ACBD3 (GCP60, GOCAP1, GOLPH1) of 528 aas and one N-terminal TMS.  It is involved in the maintenance of the Golgi structure by interacting with giantin, affecting protein transport between the endoplasmic reticulum and Golgi (Sohda et al. 2001).

ACBD3 of Homo sapiens

 
9.B.17.2.4

FYVE and coiled-coil domain-containing protein 1, FYCO1, of 1478 aas and possibly two TMSs near the C-terminus of the protein.  A mutation in the FYCO1 gene causes congenital cataracts (Mei et al. 2022).

FYCO1 of Homo sapiens