Oxysterol-binding Protein
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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 7-9 kDa found in higher plant tissues. As its name implies, lipid transfer proteins facilitate the shuttling of phospholipids and ...
(LTPs). Concretely, they constitute a family of
sterol A sterol is any organic compound with a Skeletal formula, skeleton closely related to Cholestanol, cholestan-3-ol. The simplest sterol is gonan-3-ol, which has a formula of , and is derived from that of gonane by replacement of a hydrogen atom on ...
and
phosphoinositide Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...
binding and transfer proteins in
eukaryotes The eukaryotes ( ) constitute the domain of Eukaryota or Eukarya, organisms whose cells have a membrane-bound nucleus. All animals, plants, fungi, seaweeds, and many unicellular organisms are eukaryotes. They constitute a major group of ...
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 Redox, oxidation involving enzymes and / or pro-oxidants. Such compounds play important roles in various biological processes such as cholesterol homeostasis, lipid metabolism (sphingolipids, ...
, 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 (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...
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 A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...
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 Redox, oxidation involving enzymes and / or pro-oxidants. Such compounds play important roles in various biological processes such as cholesterol homeostasis, lipid metabolism (sphingolipids, ...
is a
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
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 organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and others. The fu ...
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; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
.


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 se ...
and
structural motif In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a common three-dimensional structure that appears in a variety of different, evolutionarily unrelated molecules. A structural motif does not have t ...
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,
lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In ani ...
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 multidomain enzymes, 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. Ultrastructure, 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 clea ...
. 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 ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
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 (also known as chronic disease or chronic illness) 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 ...
, such as
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
,
neurodegenerative A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...
diseases,
inflammatory bowel diseases Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...
, age-related macular degeneration and other pathological conditions related to
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
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