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FLASH GENE

Symbol

VAPB

contributors: mct/npt/pgu - updated : 05-01-2017

HGNC name	VAMP (vesicle-associated membrane protein)-associated protein B and C
HGNC id	12649

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_004738 6 - 3689 NP_004729 27.2 243 - 2008 18555774 variant c VAPC 3 splicing 1833 isoform c 11.1 99 - 2010 20227395 truncated lacking exons 3–5, plays an important role in the propagation of hepatitis C virus NM_001195677 3 - 7587 NP_001182606 - 99 - 2010 20227395 VAPB-2 VAPB-3 5 - - - - - 2010 20227395 lacking exon 3 VAPB3-4 4 - - - - - 2010 20227395 Lacking exons 3-4 VAPB4-5 4 - - - - - 2010 20227395 Lacking exons 4-5 VAPB2-3-4 3 - - - - - 2010 20227395 Lacking exons 2-3-4

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine adrenal gland       highly Nervous spinal cord       predominantly Reproductive female system ovary     highly   male system prostate

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal   predominantly Nervous central

cell lineage
cell lines	lymphoma
fluid/secretion

at STAGE

physiological period

embryo

Text	expressed early in development in pluripotent stem cells

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal MSP (major sperm protein) domain, containing an FFAT-motif binding site (correct distribution of the proline residues would be critical for the correct fold of the MSP domain which is required for recognition of the FFAT motif of its partner), and a VAP consensus sequence (VCS) (
	a transmembrane domain
	an amphipathic helical structure
	a central coiled-coil protein- protein interaction motif
	a hydrophobic C-terminus acting as a membrane-anchor
	(endoplasmatic reticulum membrane anchored C-terminal domain)

mono polymer

homomer , heteromer , dimer

HOMOLOGY

interspecies	homolog to Drosophila DVAP-33A
	homolog to C. elegans VPR-1

intraspecies

homolog to VAPA (60 p100)

Homologene

FAMILY

CATEGORY

secretory , signaling

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,organelle,lysosome
	intracellular,cytoplasm,cytosolic,vesicle
text	type IV membrane protein
	is an integral endoplasmic reticulum (ER) protein whose amino-terminus projects into the cytosol
	is an integral membrane protein localized to the endoplasmic reticulum (ER)

basic FUNCTION	may be involved in vesicle trafficking
	playing a a possible role in synaptic homeostasis, by coordinating structural remodeling and post-synaptic sensitivity to neurotransmitter to ensure synaptic efficacy
	may act as docking sites for cytoplasmic factors to interact with the ER
	may have structural and regulatory functions based on interactions of the MSP domain
	plays an important role in the replication of the hepatitis C virus genome
	can bind to lipid-binding proteins
	VAPB function is required for transport to the nuclear envelope
	role of VAPB in tumor promotion in human breast cancer
	both VAPB and YIF1A are important for ER-to-Golgi transport and missorting of YIF1A may contribute to VAPB-associated motor neuron disease
	VAPB and the related protein VAPA form homo- and heterodimers that are anchored in the endoplasmic reticulum membrane and can interact with protein partners carrying a FFAT motif
	is a tail-anchored protein in the endoplasmic reticulum (ER)
	functions as an adaptor protein to recruit target proteins to the ER and execute various cellular functions, lipid transport, membrane traffic, ER stress
	binding of VAPB to RAB3GAP1 is implicated in the regulation of nuclear envelope formation through ERGIC
	VAPB and RMND3 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-RMND3 interaction

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

heterodimer with VAPA

INTERACTION

DNA

RNA

small molecule

protein	interact with VAMP1 and VAMP2
	interact directly with components of ER homeostatic and stress signaling systems and may therefore be parts of a previously unidentified regulatory pathway (mis-function of such regulatory systems may contribute to the pathological mechanisms of degenerative motor neuron disease)
	interact with lipid-binding proteins carrying a short motif containing two phenylalanines in an acidic tract (FFAT motif) and targets them to the cytosolic surface of the endoplasmic reticulum (ER)
	VAPB interacts with the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein 51 (RMDN3)
	VAPB strongly affects the distribution of YIF1A and is required for intracellular membrane trafficking into dendrites and normal dendritic morphology
	VAPB/ALS8 interacts with FFAT-like proteins including the VCP cofactor FAF1 and the ASNA1 ATPase
	directly binds to RAB3 GTPase activating protein 1 (RAB3GAP1), the catalytic subunit of RAB3GAP, through the two phenylalanines (FF) in an acidic tract (FFAT)-like motif of RAB3GAP1
	VAPB-RMDN3 tethers regulate macroautophagy/autophagy
	VAPA, VAPB are endoplasmic reticulum (ER)-resident integral membrane protein that controls a nonvesicular mode of ceramide and cholesterol transfer from the ER to the Golgi complex by interacting with COL4A3BP and oxysterol-binding protein (OSBP), respectively
	the mechanism by which the VAPB-RMDN3 tethers regulate autophagy involves their role in mediating delivery of Ca2+ to mitochondria from ER stores
	VAPB and RMND3 localise and form contacts at synapses, and stimulating neuronal activity increases ER-mitochondria contacts and the VAPB-RMND3 interaction

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

ALS8 , SMAPA

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --low   reduced levels of VAP family proteins result in decreased ER anchoring of lipid-binding proteins and cause motor neuron degeneration constitutional     --low   reduced levels of VAPB might be an initial defect leading to ALS8 pathogenesis constitutional     --low   loss of either VAPB or RMDN3 perturbs uptake of Ca(2+) by mitochondria following release from ER stores

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurology neurodegenerative   optimal levels of VAPB may play a central role in the pathogenesis of ALS8, in agreement with the observed reduction of VAPB in sporadic ALS

ANIMAL & CELL MODELS