VAMP-Associated Protein A ( or

Vesicle-Associated Membrane Protein Vesicle associated membrane proteins (VAMPs) are a family of SNARE proteins with similar structure, and are mostly involved in vesicle fusion. * VAMP1 and VAMP2 proteins known as synaptobrevins are expressed in brain and are constituents o ...

-Associated Protein A) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''VAPA''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Together with

VAPB Vesicle-associated membrane protein-associated protein B/C is a protein that in humans is encoded by the ''VAPB'' gene. The VAPB gene is found on the 20th human chromosome. Together with VAPA, it forms the VAP protein family. Function The ...

and VAPC it forms the VAP protein family. They are integral endoplasmic reticulum membrane proteins of the type II and are ubiquitous among eukaryotes. VAPA is ubiquitously expressed in human tissues and is thought to be involved in membrane trafficking by interaction with

SNARE SNARE proteins – "Soluble NSF attachment protein, SNAP REceptors" – are a large protein family consisting of at least 24 members in yeasts and more than 60 members in mammalian and plant cells. The primary role of SNARE proteins is to m ...

s, in regulation of lipid transport and metabolism, and in the Unfolded Protein Response ( UPR).

Protein structure

The protein is divided in three different domains. First, an N-terminal

beta-sheet The beta sheet (β-sheet, also β-pleated sheet) is a common structural motif, motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone chain, backbon ...

with an immunoglobulin-like fold that shares homology with the Nematode major sperm protein ( MSP). Secondly, a central

coiled-coil A coiled coil is a structural motif in proteins in which two to seven alpha-helices are coiled together like the strands of a rope. ( Dimers and trimers are the most common types.) They have been found in roughly 5-10% of proteins and have a v ...

domain. Then finally a C-terminal

transmembrane domain A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...

(TMD) which is usually present in proteins of the

t-SNARE SNARE proteins – " SNAP REceptors" – are a large protein family consisting of at least 24 members in yeasts and more than 60 members in mammalian and plant cells. The primary role of SNARE proteins is to mediate the fusion of vesicles ...

superfamily and has been found in other proteins associated with vesicular transport. VAPA can form homo-dimers and also hetero dimers with VAPB by interactions through their (TMD).

Intracellular Localisation

Because of its ubiquitous expression, the intracellular localisation and function of VAPA may vary between cell types. It is however mainly located in the ER, Golgi apparatus and the Vesicular Tubular Compartment or ER-Golgi Intermediate Compartment, an organelle of eukaryotic cells consisting in fused ER-derived vesicles that transports proteins from the ER to the Golgi apparatus.

Interactions

VAPA has been documented to interact with three different groups of proteins: proteins associated with vesicle traffic and fusion, proteins containing the

FFAT motif A FFAT motif (FFAT being an acronym for two phenylalanines (FF) in an acidic tract) is a protein sequence motif of six defined amino acids plus neighbouring residues that binds to proteins in the VAP protein family. Initial definition The classic ...

and viral proteins.

Vesicle traffic and fusion

VAPA is able to bind a range of SNARE proteins including syntaxin1A, rbet1 and rsec22. It also binds to proteins associated with membrane fusion machinery such as alphaSNAP and

NSF NSF may stand for: Political organizations *National Socialist Front, a Swedish National Socialist party *NS-Frauenschaft, the women's wing of the former German Nazi party * National Students Federation, a leftist Pakistani students' political g ...

.These interaction suggest that VAPA could have a general role in the regulation of the function of these proteins that are mainly involved in membrane fusion

Viral Proteins

VAP proteins have been found to be essential host factors for several viruses. VAP proteins binds with non-structural proteins of the hepatitis C virus

NS5A Nonstructural protein 5A (NS5A) is a zinc-binding and proline-rich hydrophilic phosphoprotein that plays a key role in Hepatitis C virus RNA replication. It appears to be a dimeric form without ''trans''-membrane helices. Structure NS5A is deri ...

and

NS5B Nonstructural protein 5B (NS5B) is a viral protein found in the hepatitis C virus (HCV). It is an RNA-dependent RNA polymerase, having the key function of replicating HCV's viral RNA by using the viral positive RNA strand as a template to catalyze ...

allowing the RNA replication machinery of the virus to set up on the

lipid raft The cell membrane, plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein Receptor (biochemistry), receptors organized in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular me ...

membrane of the host cell. VAPA also binds to several viral proteins from the

Norovirus Norovirus, also known as Norwalk virus and sometimes referred to as the winter vomiting disease, is the most common cause of gastroenteritis. Infection is characterized by non-bloody diarrhea, vomiting, and stomach pain. Fever or headaches may ...

family and is important for the virus replication efficiency. The non-structural proteins NS1 and NS2 are able to bind VAPA thanks to sequence mimicry of the FFAT motif probably yielding the same advantage to viral replication as for hepatitis C virus.

FFAT motif

The N-terminal MSP-homologous part of VAPA is able to bind to the FFAT motif, a particular sequence motif shared by several lipid binding proteins including oxysterol-binding protein (

OSBP Oxysterol-binding protein 1 is a protein that in humans is encoded by the ''OSBP'' gene. Function Oxysterol-binding protein (OSBP) is an intracellular protein that was identified as a cytosolic 25-hydroxycholesterol-binding protein. OSBP is a ...

Function

One of its proposed functions is to slow down the lipid flow back towards the ER when protein misfolding occurs, in order to reduce the amount of stress triggered by the UPR. The VAP would regulate this process by inhibiting membrane contact.

Associated Diseases

The P56S SNP in the MSP domain of VAPB is involved in the onset of Lou Gehrig's disease also called amyotrophic lateral sclerosis (

ALS Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, terminal neurodegenerative disorder that results in the progressive loss of both upper and low ...

) where the patient loses muscle control and function. The degenerescence of motor neurons observed in such condition could to be due to the inability of VAPB to regulate the lipid function around the ER and the subsequent consequences on cell function.