The oxysterol-binding protein (OSBP)-related proteins (ORPs) are a family of
lipid transfer proteins
Plant lipid transfer proteins, also known as plant LTPs or PLTPs, are a group of highly- conserved proteins of about 7-9kDa found in higher plant tissues. As its name implies, lipid transfer proteins facilitate the shuttling of phospholipids and o ...
(LTPs). Concretely, they constitute a family of
sterol
Sterol is an organic compound with formula , whose molecule is derived from that of gonane by replacement of a hydrogen atom in position 3 by a hydroxyl group. It is therefore an alcohol of gonane. More generally, any compounds that contain the go ...
and
phosphoinositide
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
binding and transfer proteins in
eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
that are
conserved from yeast to humans. They are
lipid-binding proteins implicated in many cellular processes related with
oxysterol
An oxysterol is a derivative of cholesterol obtained by oxidation involving enzymes and / or pro-oxidants. Such compounds play important roles in various biological processes such as cholesterol homeostasis, lipid metabolism (sphingolipids, fatty a ...
, including signaling, vesicular trafficking, lipid metabolism, and nonvesicular sterol transport.
In
yeast
Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are estimated to constitut ...
cells, some ORPs might function as sterol or lipid transporters though yeast strains lacking ORPs do not have significant defects in sterol transport between 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) 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
Mammals () are a group of vertebrate animals constituting the class (biology), class Mammalia (), characterized by the presence of mammary glands which in Female#Mammalian female, females produce milk for feeding (nursing) their young, a ...
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
An oxysterol is a derivative of cholesterol obtained by oxidation involving enzymes and / or pro-oxidants. Such compounds play important roles in various biological processes such as cholesterol homeostasis, lipid metabolism (sphingolipids, fatty a ...
is a
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
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
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
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
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
.
Structure
All oxysterol related proteins (ORP) contain 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
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of s ...
and
structural motif
In a polymer, chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common Biomolecular structure#Tertiary structure, three-dimensional structure that appears in a variety of different, evolutionarily unrel ...
s types are found in OSBP-ORPs.
FFAT motif
This is two phenylalanines in an acidic tract. It is bound by the endoplasmic reticulum to a lot of proteins involved in lipid metabolism. It is contained in most mammalian ORPs and in about 40% of yeast's ORPs.
Ankyrin motif
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).
Transmembrane domain
It is only present in some human proteins. It is a hydrophobic region which holds the protein to the cell membrane.
PH (pleckstrin homology) domain
It binds phosphoinositides, usually only the ones which have low affinity and other ligands. It also recognizes organelles enriched in the PIPs.
GOLD (Golgi dynamics) domain
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.
ORD (OSBP-related domain)
It contains 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.
Main functions
As part of the Lipid Transfer proteins (LTPs) family, ORPs have different and variate functions. This functions include signaling,
vesicular trafficking Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory c ...
,
lipid metabolism
Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In anim ...
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 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
A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain.
Protein c ...
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 Membrane contact sites (MCS) are close appositions between two organelles. Ultrastructural studies typically reveal an intermembrane distance in the order of the size of a single protein, as small as 10 nm or wider, with no clear upper limit. ...
.
2-ORPs help establish 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 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.
OSBP-ORPs human proteins
In humans there are 12 ORP genes, and splicing generates 16 different protein products.
OSBP-ORPs yeast proteins
In yeast (''
Saccharomyces cerevisiæ'') we can find 7 ORP genes called OSH1-7, but they have some additional names as well.
Role in disease
Some oxysterols have been found to contribute to the
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
and oxidative damage as well as in cell death in the appearance and especially the development of some of the most important
chronic diseases
A chronic condition is a health condition or disease that is persistent or otherwise long-lasting in its effects or a disease that comes with time. The term ''chronic'' is often applied when the course of the disease lasts for more than three mo ...
, such as
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
,
neurodegenerative
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
diseases,
inflammatory bowel diseases
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine and large intestine, as well a ...
, age-related macular degeneration and other pathological conditions related to
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
absorption.
Besides, a recent study suggests a method of screening and diagnosing Niemann-Pick C disease by plasma oxysterol screening, which is found to be less invasive, more sensitive and specific and more economical strategy than the current practice.
References
{{InterPro content, IPR000648
Protein domains
Peripheral membrane proteins