Misplaced Pages

#318681

20-504: 2RR3 9218 30960 ENSG00000101558 ENSMUSG00000024091 Q9P0L0 Q9WV55 NM_003574 NM_194434 NM_013933 NM_001355402 NP_003565 NP_919415 NP_038961 NP_001342331 VAMP-Associated Protein A ( or Vesicle-Associated Membrane Protein -Associated Protein A) is a protein that in humans is encoded by the VAPA gene . Together with VAPB and VAPC it forms

40-524: A core lipid-binding domain (ORD), which has a characteristic amino acids sequence, EQVSHHPP. The most studied ORP are human and yeast ones, and the only OSBP-ORP whose structure is completely known is the Kes1p, also called Osh4p, a yeast one. Six different protein domains and structural motifs types are found in OSBP-ORPs. This is two phenylalanines in an acidic tract. It is bound by the endoplasmic reticulum to

60-526: A few ORPs actually bind sterols and collectively yeast ORPs are dispensable for sterol transfer in vivo. They are also part of Golgi-to-plasma membrane vesicular trafficking, but their role is not clear yet. In mammalian, ORPs participate as sterol sensors. This sensors regulate the assembly of protein complexes when cholesterol levels fluctuate. They use the following mechanisms: 1 -They could extract and deliver lipids from one membrane to another. Probably at membrane contact site . 2 -ORPs help establish

80-409: A lot of proteins involved in lipid metabolism. It is contained in most mammalian ORPs and in about 40% of yeast's ORPs. It is thought that it takes part in protein-protein interactions, but it is not known for certain. In some proteins, it also contributes to the localization of each protein to a membrane contact site (zone of close contact between the endoplasmic reticulum and a second organelle). It

100-643: Is a cholesterol metabolite that can be produced through enzymatic or radical processes. Oxysterols, that are the 27-carbon products of cholesterol oxidation by both enzymic and non-enzymic mechanisms, constitute a large family of lipids involved in a plethora of physiological processes. Studies identifying the specific cellular targets of oxysterol indicate that several oxysterols may be regulators of cellular lipid metabolism via control of gene transcription. In addition, they were shown to be involved in other processes such as immune regulatory functions and brain homeostasis . All oxysterol related proteins (ORP) contain

120-618: Is apposed with other organelle limiting membranes. Yeast ORPs also participate in vesicular trafficking, in which they affect Sec14-dependent Golgi vesicle biogenesis and, later in post-Golgi exocytosis, they affect exocyst complex-dependent vesicle tethering to the plasma membrane. In mammalian cells, some ORPs function as sterol sensors that regulate the assembly of protein complexes in response to changes in cholesterol levels. By that means, ORPs most likely affect organelle membrane lipid compositions, with impacts on signaling and vesicle transport, but also cellular lipid metabolism. Oxysterol

140-476: Is only present in some human proteins. It is a hydrophobic region which holds the protein to the cell membrane. It binds phosphoinositides, usually only the ones which have low affinity and other ligands. It also recognizes organelles enriched in the PIPs. As well as Ankyrin motif, it probably mediates interactions between proteins. It is only found in one yeast protein and it is not found in any human ORP. It contains

160-561: The FFAT motif and viral proteins. 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 .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 VAP proteins have been found to be essential host factors for several viruses. VAP proteins binds with non-structural proteins of

180-624: 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 SNAREs , in regulation of lipid transport and metabolism, and in the Unfolded Protein Response ( UPR ). The protein is divided in three different domains. First, an N-terminal beta-sheet with an immunoglobulin-like fold that shares homology with

200-488: The inflammation and oxidative damage as well as in cell death in the appearance and especially the development of some of the most important chronic diseases , such as atherosclerosis , neurodegenerative diseases, inflammatory bowel diseases , age-related macular degeneration and other pathological conditions related to cholesterol absorption. Besides, a recent study suggests a method of screening and diagnosing Niemann-Pick C disease by plasma oxysterol screening, which

220-722: The EQVSHHPP sequence. It has an hydrophobic pocket that binds a sterol and also contains multiple membrane binding surfaces which permit the protein to have the ability to cause liposome aggregation. As part of the Lipid Transfer proteins (LTPs) family, ORPs have different and variate functions. This functions include signaling, vesicular trafficking , lipid metabolism and nonvesicular sterol transport. ORPs have been studied in many organisms cells as human cells or yeast. In yeast, where organelle membranes are closely apposed it has been proposed that ORPs work as sterol transporters, though only

SECTION 10

#1732902289319

240-699: The ER and the subsequent consequences on cell function. 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 . This membrane protein –related article is a stub . You can help Misplaced Pages by expanding it . Oxysterol-binding protein In yeast cells, some ORPs might function as sterol or lipid transporters though yeast strains lacking ORPs do not have significant defects in sterol transport between

260-465: The Nematode major sperm protein ( MSP ). Secondly, a central coiled-coil domain. Then finally a C-terminal transmembrane domain (TMD) which is usually present in proteins of the t-SNARE 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). Because of its ubiquitous expression,

280-503: The UPR. The VAP would regulate this process by inhibiting membrane contact. 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 ) 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

300-402: The endoplasmic reticulum and the plasma membrane. Although sterol transfer is proposed to occur at regions where organelle membranes are closely apposed, disruption of endoplasmic reticulum-plasma membrane contact sites do not have major effects on sterol transfer, though phospholipid homeostasis is perturbed. Various ORPs confine at membrane contacts sites (MCS), where endoplasmic reticulum (ER)

320-544: The hepatitis C virus NS5A and NS5B allowing the RNA replication machinery of the virus to set up on the lipid raft membrane of the host cell. VAPA also binds to several viral proteins from the Norovirus 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

340-620: 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. VAPA has been documented to interact with three different groups of proteins: proteins associated with vesicle traffic and fusion, proteins containing

360-990: The membrane is regulated by ORPs in two ways. One way is by presenting a lipid to a second lipid-binding protein. (5) Another way is preventing the lipid-binding protein from accessing a lipid in the membrane. This two mechanisms are not mutually exclusive so ORPs might use both. In humans there are 12 ORP genes, and splicing generates 16 different protein products. (OSBP1) (KIAA1664, ORP-4, ORP4) (ORP-1, ORP1) "(KIAA0772, ORP2)" (ORP-3, ORP3, KIAA0704) (KIAA1534, ORP5) (ORP6) (ORP7, MGC71150) (OSBP10, ORP8, MST120, MSTP120) (ORP9, OSBP4) (ORP10, OSBP9) (ORP-11, ORP11, FLJ13012, FLJ13164) In yeast ( Saccharomyces cerevisiæ ) we can find 7 ORP genes called OSH1-7, but they have some additional names as well. (SWH1, YAR042W, YAR044W) (YDL019C, D2845) (YHR073W) (KES1, YPL145C, LPI3C, P2614) (HES1, YOR237W, O5234) (YKR003W, YK102) (YHR001W) Some oxysterols have been found to contribute to

380-474: The membrane when transient changes in the distribution of lipids occur. They add or remove lipids within different regions of the membrane. The exclusion of certain lipids in particular regions drive to processes such as membrane binding or signaling. 3 -They work as lipid sensors altering interactions with other proteins due to binding or releasing lipid ligands. It occurs mainly at inally organelle contact sites. 4 -The access of other lipid-binding proteins to

400-430: The same advantage to viral replication as for hepatitis C virus. 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 ). 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

#318681