Low-density lipoprotein receptor-related protein 5 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''LRP5''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
LRP5 is a key component of the LRP5/
LRP6
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the ''LRP6'' gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
Structure
LRP6 is a t ...
/
Frizzled
Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.
Species distribution
Fri ...
co-receptor group that is involved in
canonical Wnt pathway. Mutations in LRP5 can lead to considerable changes in bone mass. A
loss-of-function mutation causes
osteoporosis pseudoglioma syndrome with a decrease in bone mass, while a
gain-of-function
Gain-of-function research (GoF research or GoFR) is medical research that genetically alters an organism in a way that may enhance the biological functions of gene products. This may include an altered pathogenesis, transmissibility, or host ...
mutation causes drastic increases in bone mass.
Structure
LRP5 is a transmembrane low-density
lipoprotein
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
that shares a similar structure with
LRP6
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the ''LRP6'' gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
Structure
LRP6 is a t ...
. In each protein, about 85% of its 1600-
amino-acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ami ...
length is extracellular. Each has four β-propeller motifs at the amino terminal end that alternate with four
epidermal growth factor
Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds.
EGF was originally descr ...
(EGF)-like repeats. Most extracellular ligands bind to LRP5 and LRP6 at the β-propellers. Each protein has a single-pass, 22-amino-acid segment that crosses the cell membrane and a 207-amino-acid segment that is internal to the cell.
Function
LRP5 acts as a co-receptor with LRP6 and the
Frizzled
Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.
Species distribution
Fri ...
protein family members for transducing signals by
Wnt proteins
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...
through the
canonical Wnt pathway.
This protein plays a key role in skeletal homeostasis.
Transcription
The LRP5
promoter contains binding sites for
KLF15
Krüppel-like factor 15 is a protein that in humans is encoded by the ''KLF15'' gene in the Krüppel-like factor family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.
Expression
Activated glucocorticoid recepto ...
and
SP1.
In addition, 5' region of the LRP5 gene contains four
RUNX2
Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the ''RUNX2'' gene. RUNX2 is a key transcription factor associated with osteoblast differentia ...
binding sites.
LRP5 has been shown in mice and humans to inhibit expression of
TPH1
Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the ''TPH1'' gene.
TPH1 was first discovered to synthesize serotonin in 1988 and was thought that there only was a single ''TPH'' gene until ...
, the rate-limiting biosynthetic enzyme for
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
in enterochromaffin cells of the
duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
and that excess plasma serotonin leads to inhibition in bone. On the other hand, one study in mouse has shown a direct effect of Lrp5 on bone.
Interactions
LRP5 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
AXIN1
Axin-1 is a protein that in humans is encoded by the ''AXIN1'' gene.
Function
This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded prote ...
.
Canonical
WNT signals
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...
are transduced through
Frizzled
Frizzled is a family of atypical G protein-coupled receptors that serve as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.
Species distribution
Fri ...
receptor and LRP5/
LRP6
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the ''LRP6'' gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
Structure
LRP6 is a t ...
coreceptor to downregulate GSK3beta (
GSK3B
Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased suscept ...
) activity not depending on Ser-9
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
.
Reduction of canonical Wnt signals upon depletion of LRP5 and LRP6 results in p120-
catenin
Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells. The first two catenins that were identified became known as α-catenin and β-catenin. α-Catenin can bind to β-catenin and can also bin ...
degradation.
Clinical significance
The
Wnt signaling pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling p ...
was first linked to bone development when a
loss-of-function mutation in LRP5 was found to cause osteoporosis-pseudoglioma syndrome. Shortly thereafter, two studies reported that
gain-of-function
Gain-of-function research (GoF research or GoFR) is medical research that genetically alters an organism in a way that may enhance the biological functions of gene products. This may include an altered pathogenesis, transmissibility, or host ...
mutations in LRP5 caused high bone mass. Many bone density related diseases are caused by mutations in the LRP5 gene. There is controversy whether bone grows through Lrp5 through bone or the intestine.
The majority of the current data supports the concept that bone mass is controlled by LRP5 through the osteocytes.
Mice with the same Lrp5 gain-of-function mutations as also have high bone mass.
The high bone mass is maintained when the mutation only occurs in limbs or in cells of the osteoblastic lineage.
Bone
mechanotransduction
In cellular biology, mechanotransduction ('' mechano'' + '' transduction'') is any of various mechanisms by which cells convert mechanical stimulus into electrochemical activity. This form of sensory transduction is responsible for a number of ...
occurs through Lrp5 and is suppressed if Lrp5 is removed in only
osteocytes
An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide and ...
. There are promising osteoporosis clinical trials targeting
sclerostin
Sclerostin is a protein that in humans is encoded by the ''SOST'' gene.
Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative ...
, an osteocyte-specific protein which inhibits Wnt signaling by binding to Lrp5.
An alternative model that has been verified in mice and in humans is that Lrp5 controls bone formation by inhibiting expression of
TPH1
Tryptophan hydroxylase 1 (TPH1) is an isoenzyme of tryptophan hydroxylase which in humans is encoded by the ''TPH1'' gene.
TPH1 was first discovered to synthesize serotonin in 1988 and was thought that there only was a single ''TPH'' gene until ...
, the rate-limiting biosynthetic enzyme for
serotonin
Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
, a molecule that regulates bone formation, in enterochromaffin cells of the
duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
and that excess plasma serotonin leads to inhibition in bone. Another study found that a different Tph1-inhibitor decreased serotonin levels in the blood and intestine, but did not affect bone mass or markers of bone formation.
LRP5 may be essential for the development of retinal vasculature, and may play a role in capillary maturation.
Mutations in this gene also cause
familial exudative vitreoretinopathy
Familial exudative vitreoretinopathy (FEVR, pronounced as fever) is a genetic disorder affecting the growth and development of blood vessels in the retina of the eye. This disease can lead to visual impairment and sometimes complete blindness in o ...
.
A glial-derived extracellular ligand, Norrin, acts on a transmembrane receptor,
Frizzled4, a coreceptor, Lrp5, and an auxiliary membrane protein,
TSPAN12
Tetraspanin-12 (Tspan-12) also known as tetraspan NET-2 (NET2) or transmembrane 4 superfamily member 12 (TM4SF12) is a tetraspanin protein that in humans is encoded by the ''TSPAN12'' gene. Tetraspanin-12 is found in the membrane of a variety of c ...
, on the surface of developing endothelial cells to control a transcriptional program that regulates endothelial growth and maturation.
LRP5 knockout in mice led to increased plasma cholesterol levels on a high-fat diet because of the decreased hepatic clearance of
chylomicron
Chylomicrons (from the Greek χυλός, chylos, meaning ''juice'' (of plants or animals), and micron, meaning ''small particle''), also known as ultra low-density lipoproteins (ULDL), are lipoprotein particles that consist of triglycerides (85 ...
remnants. When fed a normal diet, LRP5-deficient mice showed a markedly impaired
glucose tolerance
Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesit ...
with marked reduction in intracellular
ATP and
Ca2+ in response to glucose, and impairment in glucose-induced insulin secretion.
IP3 production in response to glucose was also reduced in LRP5—islets possibly caused by a marked reduction of various transcripts for genes involved in glucose sensing in LRP5—islets. LRP5-deficient islets lacked the
Wnt-3a-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.
In
osteoarthritic chondrocyte
Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
s the Wnt/beta-catenin pathway is activated with a significant up-regulation of beta-catenin mRNA expression. LRP5 mRNA and protein expression are also significantly up-regulated in osteoarthritic cartilage compared to normal cartilage, and LRP5 mRNA expression was further increased by
vitamin D
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...
. Blocking LRP5 expression using
siRNA
Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating wi ...
against LRP5 resulted in a significant decrease in
MMP13
Collagenase 3 is an enzyme that in humans is encoded by the ''MMP13'' gene. It is a member of the matrix metalloproteinase (MMP) family. Like most MMPs, it is secreted as an inactive pro-form. MMP-13 has an predicted molecular weight around 54 kDa. ...
mRNA and protein expressions. The
catabolic
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
role of LRP5 appears to be mediated by the Wnt/beta-catenin pathway in human osteoarthritis.
The polyphenol curcumin increases the mRNA expression of LRP5.
Mutations in LRP5 cause
polycystic liver disease
Polycystic liver disease (PLD) usually describes the presence of multiple cysts scattered throughout normal liver tissue. PLD is commonly seen in association with autosomal-dominant polycystic kidney disease, with a prevalence of 1 in 400 to 1000, ...
.
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Familial Exudative Vitreoretinopathy, Autosomal Dominant
{{Lipoprotein metabolism