LDL-receptor-related protein-associated protein
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Low density lipoprotein receptor-related protein-associated protein 1 also known as LRPAP1 or RAP is a chaperone protein which in humans is encoded by the LRPAP1 gene.


Function

LRPAP1 is involved with trafficking of certain members of the
LDL receptor The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor ...
family including LRP1 and LRP2. It is a
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
that binds to the alpha-2-macroglobulin receptor, as well as to other members of the low density lipoprotein
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 ...
family. It acts to inhibit the binding of all known
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
for these receptors, and may prevent receptor
aggregation Aggregation may refer to: Business and economics * Aggregation problem (economics) * Purchasing aggregation, the joining of multiple purchasers in a group purchasing organization to increase their buying power * Community Choice Aggregation, the ...
and degradation in the endoplasmic reticulum, thereby acting as a molecular chaperone. It may be under the regulatory control of calmodulin, since it is able to bind
calmodulin Calmodulin (CaM) (an abbreviation for calcium-modulated protein) is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells. It is an intracellular target of the secondary messenger Ca2+, and the bind ...
and be phosphorylated by calmodulin-dependent
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
II.


Interactions

LDL-receptor-related protein-associated protein 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 LRP2.


Mutations and diseases related to LRPAP1

Lipid metabolizing proteins may elevate susceptibility to dementia leading to differences in genetic makeup. PCR-restriction fragment length polymorphism technique is used for genotyping of
LRPAP1 Low density lipoprotein receptor-related protein-associated protein 1 also known as LRPAP1 or RAP is a chaperone protein which in humans is encoded by the LRPAP1 gene. Function LRPAP1 is involved with trafficking of certain members of the LD ...
intron 5 insertion/deletion. The studies suggested that DD genotype and *D allele of LRPAP gene showed increased frequency for degenerative dementias on comparison with the control group and that LRPAP1-D allele remarkably increases the vulnerability to degenerative dementias. On genotyping of LRPAP1 polymorphism is observed because of 37 base pair insertion in intron 5. Also insertion allele being larger than deletion allele makes possible in detecting difference by gel electrophoresis. Suppression of receptor-binding domain of LRP LDLR is due to overexpression of LRPAP (the protein product of LRPAP gene). LRP gives protection across LDL by LRPAP and its downregulation may be subjected for an elevation of LDL and Ab-related neuronal toxicity as LRP supports in binding of ligand and internalization of LRP ligands like apo-E-enriched LDL cholesterol and Ab protein. Insertion/deletion is an intronic polymorphism of LRPAP gene, Influencing DD genotype and D allele for the synthesis of LRPAP protein can be lrp-mediated mechanism contributing to dementia. Concern for developing sensitivity for dementia is because of several shared common genetic platforms and DD genotype or D allele of LRPAP gene may be one such. So on 37-bp insertion/deletion that was studied as an intronic polymorphism, it could be having an unintended pursuit for lipid receptor protein by regulation of LRPAP expression, or it could be in linkage disequilibrium in addition to other biologically relevant polymorphism in the LRPAP1 or an adjacent gene in chromosome 4. Results being consistent with earlier study where the authors have endowed deletion allele frequency clearly high in late-onset Alzheimer’s disease patients on comparison with non-demented aged controls. Mendelian forms of
myopia Near-sightedness, also known as myopia and short-sightedness, is an eye disease where light focuses in front of, instead of on, the retina. As a result, distant objects appear blurry while close objects appear normal. Other symptoms may include ...
has been identified in four consanguineous families and are the likely causal mutations implementing exome /autozygome investigated to recognize homozygous truncating variants in LRPAP1. Influencing TGF-β activity, chaperone of LRP1 is encoded by LRPAP1.Notably salient deficiency of LRP1 and upregulation of TGF-β in affected individuals cells, the known data being consistent on the importance of TGF-β in remodeling for the sclera of myopia and the increased frequency in individuals for myopia having
Marfan syndrome Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes. They also typically have exceptionally flexible joints a ...
which has characteristics of upregulated TGF-β signaling. Analysizing the absence of the normal protein was done with immunoblot for affected individuals having LRPAP1 mutations revealing the mutations in
LRPAP1 Low density lipoprotein receptor-related protein-associated protein 1 also known as LRPAP1 or RAP is a chaperone protein which in humans is encoded by the LRPAP1 gene. Function LRPAP1 is involved with trafficking of certain members of the LD ...
probability of loss-of-function mutations. Encoding (Low Density Lipoprotein Receptor-Related Protein Associated protein 1) LRPAP is a largely expressed gene, and a 357 amino acid protein thought as a chaperone binding and protecting the lipoproteins receptor-related proteins LRP1 and LRP2. A model suggested by a study wherein LRPAP1 leading to deficiency of LRP1 which was responsible to perturbation of TGF-β regulation and might cause abnormal ECM remodeling in the eye development. On observation for increasing axial length was one of the salient features of
Marfan syndrome Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes. They also typically have exceptionally flexible joints a ...
also resulting in TGF-β supported the model. Therefore, individuals having myopia responding to therapeutic strategy initiated before ECM remodeling could be considered as an approach for individuals with LRPAP1 related myopia.


References


Further reading

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External links

* {{Lipoprotein metabolism