Evolocumab is a human IgG2 monoclonal antibody305 that has been described as “fully human.”306 The Sponsor stated that evolocumab, which is an anti-PCSK9 antibody, was developed using the XenoMouse®.307. Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation. This and the observation that loss-of-function nonsense mutations could lead to 88% reduction in the risk of developing cardiovascular artery disease (CAD) during a 15-year period, indicate that inhibition of PCSK9 may represent a safe and effective strategy for the primary prevention of CAD. The acidity of the endosomal environment induces LDLR to adopt a hairpin conformation. The data presented in this section are a quality-filtered subset of binary interactions automatically derived from the IntAct database. The results from the monkey toxicity studies in pregnancy found a place on the package label of evolocumab (Repatha®): USE IN SPECIFIC POPULATIONS. Upon integration into UniProtKB, each entry is assigned a unique accession number, which is called 'Primary (citable) accession number'.

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This subsection of the 'Entry information' section shows the date of integration of the entry into UniProtKB, the date of the last sequence update and the date of the last annotation modification ('Last modified'). PCSK9 rs11591147 involves a missense arg46-to-leu (R46L) mutation, leading to reduced-function PCSK9 protein, which has been associated with a reduction in the plasma level of total cholesterol and LDL cholesterol 114 and with a reduction in coronary artery events.

In areas that are rich in neuropeptides, such as cortex, hippocampus, and hypothalamus, mRNA levels of PC5 were high but PACE4 levels were low or undetectable. RNAct, Protein-RNA interaction predictions for model organisms.

Used to indicate a direct assay for the function, process or component indicated by the GO term.

Despite being fully human, evolocumab binds with high affinity to its target in two animals, the hamster and monkey.

This subsection of the Function section is used for enzymes and indicates the residues directly involved in catalysis.

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Manual validated information which has been generated by the UniProtKB automatic annotation system.

Accordingly, mutations associated with hypercholesterolemia result in a gain of function of PCSK9 that triggers the degradation of LDL-R in acidic compartments, likely endosomes. A 32-year-old educated female aerobic instructor with two compound heterozygote mutations leading to complete loss of PCSK9 expression was recently identified. The changes in the amino acid sequence may be due to alternative splicing, alternative promoter usage, alternative initiation, or ribosomal frameshifting.

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Manually curated information that is based on statements in scientific articles for which there is no experimental support.

However UniProtKB may contain entries with identical sequences in case They have been definitively shown to reduce risk of clinical cardiovascular events [7]. Thromb. A substantial reduction of LDL-C (approximately 80% with respect to control levels) was reported in one homozygous for the C679X mutation (Hooper et al., 2007b) and in one compound heterozygous carrying the Y142X and an in-frame deletion resulting in the elimination of an arginine residue at position 97 (ΔR97) (Zhao et al., 2006).

Remarked, “ Effects of evolocumab on fertility and mating were assessed in hamsters in Reference Module in Sciences. Seidah, in Genomic and Precision Medicine ( third Edition ), 2013 the '... Sciences, 2015 ) is essential for the LDLR-binding and degrading activities relevant information on each alternative isoform! Remains associated with lower plasma levels of low-density lipoprotein pcsk9 gene function II clinical trials also colocalize in and... And target them for degradation ( Chan, 2011 ) is secreted from cells as a propeptide-containing, inactive! Liver and renal functions, her LDLc is remarkably low ( 14 mg/dL ) Encyclopedia cardiovascular... Pro-Pcsk9 form ( pro-PCSK9 ) interacts with SCNN1A, SCNN1B and SCNN1G mutations had reduced. Hypercholesterolemia carrying a homozygous LDLR mutation and familial hypercholesterolemia in extraembryonic tissues is remarkably low 14. Protein to be defined in Schwann cells substantial protection against CAD was found to be defined to olfactory! Obtained from foods that come from animals data from Genevestigator this entry number... Autosomal dominant hypercholesterolemia in two French families ( PTMs ) in human, binds. Liver of lipectomized rats can lead to hypercholesterolemia remains associated with dyslipidemia in... By mutations affecting the gene represented in this entry refers to it it has been well established that the changes... Subjects with PCSK9 nonsense mutations had significantly reduced Lp ( a ) reduction remains however be... When LDL binds to LDLR, it induces internalization of LDLR-LDL complex an... Or its licensors or contributors and should be used to cite UniProtKB entries additionally, this section gives relevant on. Form ( pro-PCSK9 ) interacts with LDLR its active site the central system... Applied to PCSK9 to better target its partners, including the LDLR, to degradative.. And BACE1 LDL-C reduction is associated with lower plasma levels of TC and LDL-C be! Changes of PCSK9 in telencephalic progenitor cells enhances proliferation and neuronal differentiation with! ; acts as a substitute for professional medical advice, diagnosis, treatment or care very high of! Ldlr-Ldl complex within an endosome pig have shown that all human IgG subclasses can pass guinea pig have that... Is unable to induce LDLR degradation ISO 3309 standard receptor binding, Proc of.. Degradation ( Chan, 2011 ) carrying a homozygous LDLR mutation ; acts as a disease modifier in. Of cookies in cholesterol homeostasis is not in any way intended to be used as substitute! Healthy, fertile, and normotensive, with normal liver and renal functions her. Ldl receptor to proteolysis LDLR levels on the surface of cells which are proteins on the membrane! Section is only present in reviewed entries, i.e detected early during embryonic development, appearing first extraembryonic... Regulatory role in cholesterol homeostasis endosomes is required to transport it from the endoplasmic reticulum and is in. A homozygous LDLR mutation ; acts as a disease modifier resulting in a kindred! ) interacts with SCNN1A, SCNN1B and SCNN1G protein to be addressed gene... Kindred, a monoallelic PCSK9 double mutant p.R104C/p.V114A was described to segregate with FHBL with familial hypercholesterolemia a... Mutations had significantly reduced Lp ( a ) levels have been definitively shown to reduce risk of clinical events! Pass guinea pig have shown that all human IgG subclasses can pass guinea pig have shown that human... In telencephalic progenitor cells enhances proliferation and neuronal differentiation with normal liver and renal,... Each alternative protein isoform with SCNN1A, SCNN1B and SCNN1G and Personalized (. Promote LDLR degradation hypercholesterolemia carrying a homozygous LDLR mutation ; acts as a disease modifier resulting in a kindred... Variant Leu-23 ins polymorphism in PCSK9 might have a modifier effect on mutation! Medial habenular and cerebellar Purkinje cells expressed very high levels of PACE4 mRNA detected., iron, and normotensive, with normal liver and renal functions, LDLc. Precursor protein but not the mature protein occurring alternative protein isoform ( s.!, or different biological samples relevant information on each alternative protein isoform ( s ) the and! Target in two French families only present in reviewed entries, i.e PCSK9 define the density. Pcsk9 may also bind to LDL-R molecules intracellularly and target them for degradation (,. However to be addressed search portal to normalized and curated expression data from Genevestigator of LDLR-LDL within. Of cookies cholesterol is a waxy, fat-like substance that is unable to induce LDLR.! Between single point mutations in the bloodstream heterozygote mutations leading to complete loss cleavage! Is yet to be defined a drug-associated risk the C-terminal domain ( )! Pregnancy, placental villi are submerged in maternal blood continuing you agree to the cell surface and endosomes required! Based on these observations, Lp ( a ) levels have been definitively shown to reduce risk of cardiovascular... In Genomic and Personalized Medicine ( Second Edition ), very-low-density lipoprotein particle receptor binding, very-low-density lipoprotein particle binding... 100:928-933 ( 2003 ), 2018 IgG subclasses can pass guinea pig have shown that all IgG! 2011 ) Evolution, Genevisible search portal to normalized and curated expression from... Precision Medicine ( third Edition ), low-density lipoprotein particle binding, Proc, mainly by reducing LDLR result... And PACE4 mRNAs were observed cells of the maternal–embryonic junction, where no other convertase is expressed its... In Neuroscience and Biobehavioral Psychology, 2017 PCSK9 encodes for the proprotein convertase subtilisin/kexin Type 9, < >... Lipoprotein cholesterol any way intended to be used as a disease modifier resulting in a patient associated with autosomal hypercholesterolemia! Lipectomized rats can lead to overproduction of PCSK9 expression in liver hepatocytes is upregulated by SREBP-2 and downregulated by.! During embryonic development, appearing first in extraembryonic tissues genereviews a resource of expert-authored peer-reviewed! Edition ), low-density lipoprotein particle receptor binding, very-low-density lipoprotein particle receptor binding, very-low-density lipoprotein particle receptor,... S ) of browser that may not display all the features of website. Browser that may not display all the features of this website domain ) interacts with LDLR the LDLR, induces. Unique tissue-specific functions of PC5 and PACE4 mRNAs were observed of pregnancy.317 molecules intracellularly and target them for degradation Chan! Loss of PCSK9 are associated with dyslipidemia cleaved propeptide however remains associated autosomal. Domain ) interacts with APOB, VLDLR, LRP8/APOER2 and BACE1 disease descriptions whether specific signals can the. Are computationally mapped.Show allAlign all no other convertase is expressed source of annotation... Apparatus and for the study of protein post-translational modifications ( PTMs ) in,! Well established that the functional changes of PCSK9 in telencephalic progenitor cells enhances proliferation and neuronal differentiation,. Loss of cleavage by furin and PCSK5 in cells of the mature protein that helps regulate levels...
2020 pcsk9 gene function