Descriptions
At cell surface, proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the LDLR and is internalized as a complex with the LDLR. PCSK9 remains bound to the LDLR and prevents the LDLR from folding over itself to adopt a closed conformation. As a consequence, the LDLR fails to recycle back to the cell membrane. PCSK9 has a function to reduce the number of LDLRs and is a key regulator of plasma LDL cholesterol levels. Accorind to a study with human PCSK9, the autoinhibitory region negatively affect the ability of PCSK9 to bind to the LDLR and fine-tune the activity of PCSK9 towards the LDLR.
Autoinhibitory domains (AIDs)
Target domain |
155-420 (Peptidase domain) |
Relief mechanism |
Cleavage |
Assay |
|
Accessory elements
No accessory elements
Autoinhibited structure
Activated structure
1 structures for A8T695
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| AF-A8T695-F1 | Predicted | AlphaFoldDB |
No variants for A8T695
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| No variants for A8T695 | |||||
No associated diseases with A8T695
6 regional properties for A8T695
| Type | Name | Position | InterPro Accession |
|---|---|---|---|
| domain | Peptidase S8/S53 domain | 180 - 418 | IPR000209 |
| domain | Peptidase S8 propeptide/proteinase inhibitor I9 | 76 - 148 | IPR010259 |
| domain | Proteinase K-like catalytic domain | 155 - 420 | IPR034193 |
| domain | Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3 | 601 - 681 | IPR041051 |
| domain | Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2 | 534 - 599 | IPR041052 |
| domain | Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 | 449 - 530 | IPR041254 |
Functions
13 GO annotations of cellular component
| Name | Definition |
|---|---|
| cell surface | The external part of the cell wall and/or plasma membrane. |
| COPII-coated ER to Golgi transport vesicle | A vesicle with a coat formed of the COPII coat complex proteins. The COPII coat complex is formed by the Sec23p/Sec24p and the Sec13p/Sec31p heterodimers. COPII-associated vesicles transport proteins from the rough endoplasmic reticulum to the Golgi apparatus (anterograde transport). |
| cytoplasm | The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures. |
| early endosome | A membrane-bounded organelle that receives incoming material from primary endocytic vesicles that have been generated by clathrin-dependent and clathrin-independent endocytosis; vesicles fuse with the early endosome to deliver cargo for sorting into recycling or degradation pathways. |
| endoplasmic reticulum | The irregular network of unit membranes, visible only by electron microscopy, that occurs in the cytoplasm of many eukaryotic cells. The membranes form a complex meshwork of tubular channels, which are often expanded into slitlike cavities called cisternae. The ER takes two forms, rough (or granular), with ribosomes adhering to the outer surface, and smooth (with no ribosomes attached). |
| extracellular space | That part of a multicellular organism outside the cells proper, usually taken to be outside the plasma membranes, and occupied by fluid. |
| Golgi apparatus | A membrane-bound cytoplasmic organelle of the endomembrane system that further processes the core oligosaccharides (e.g. N-glycans) added to proteins in the endoplasmic reticulum and packages them into membrane-bound vesicles. The Golgi apparatus operates at the intersection of the secretory, lysosomal, and endocytic pathways. |
| late endosome | A prelysosomal endocytic organelle differentiated from early endosomes by lower lumenal pH and different protein composition. Late endosomes are more spherical than early endosomes and are mostly juxtanuclear, being concentrated near the microtubule organizing center. |
| lysosome | A small lytic vacuole that has cell cycle-independent morphology found in most animal cells and that contains a variety of hydrolases, most of which have their maximal activities in the pH range 5-6. The contained enzymes display latency if properly isolated. About 40 different lysosomal hydrolases are known and lysosomes have a great variety of morphologies and functions. |
| PCSK9-AnxA2 complex | A protein complex consisting of the serine protease PCSK9 (proprotein convertase subtilisin/kexin-9) and annexin A2 (AnxA2). |
| PCSK9-LDLR complex | A protein complex consisting of the serine protease PCSK9 (proprotein convertase subtilisin/kexin-9) and a low-density lipoprotein receptor (LDLR). Interaction typically occurs through the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR, and complex formation promotes degradation of the LDLR through the endosome/lysosome pathway. |
| perinuclear region of cytoplasm | Cytoplasm situated near, or occurring around, the nucleus. |
| plasma membrane | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. |
10 GO annotations of molecular function
| Name | Definition |
|---|---|
| apolipoprotein binding | Binding to an apolipoprotein, the protein component of a lipoprotein complex. |
| apolipoprotein receptor binding | Binding to an apolipoprotein receptor. |
| low-density lipoprotein particle binding | Binding to a low-density lipoprotein particle, a lipoprotein particle that is rich in cholesterol esters and low in triglycerides, is typically composed of APOB100 and APOE, and has a density of 1.02-1.06 g/ml and a diameter of between 20-25 nm. |
| low-density lipoprotein particle receptor binding | Binding to a low-density lipoprotein receptor. |
| protein self-association | Binding to a domain within the same polypeptide. |
| serine-type endopeptidase activity | Catalysis of the hydrolysis of internal, alpha-peptide bonds in a polypeptide chain by a catalytic mechanism that involves a catalytic triad consisting of a serine nucleophile that is activated by a proton relay involving an acidic residue (e.g. aspartate or glutamate) and a basic residue (usually histidine). |
| signaling receptor inhibitor activity | Binds to and modulates the activity of a signaling receptor. |
| sodium channel inhibitor activity | Binds to and stops, prevents, or reduces the activity of a sodium channel. |
| very-low-density lipoprotein particle binding | Binding to a very-low-density lipoprotein particle, a triglyceride-rich lipoprotein particle that is typically composed of APOB100, APOE and APOCs and has a density of about 1.006 g/ml and a diameter of between 20-80 nm. |
| very-low-density lipoprotein particle receptor binding | Binding to a very-low-density lipoprotein receptor. |
25 GO annotations of biological process
| Name | Definition |
|---|---|
| apoptotic process | A programmed cell death process which begins when a cell receives an internal (e.g. DNA damage) or external signal (e.g. an extracellular death ligand), and proceeds through a series of biochemical events (signaling pathway phase) which trigger an execution phase. The execution phase is the last step of an apoptotic process, and is typically characterized by rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), plasma membrane blebbing and fragmentation of the cell into apoptotic bodies. When the execution phase is completed, the cell has died. |
| cellular response to insulin stimulus | Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an insulin stimulus. Insulin is a polypeptide hormone produced by the islets of Langerhans of the pancreas in mammals, and by the homologous organs of other organisms. |
| cellular response to starvation | Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of deprivation of nourishment. |
| cholesterol homeostasis | Any process involved in the maintenance of an internal steady state of cholesterol within an organism or cell. |
| cholesterol metabolic process | The chemical reactions and pathways involving cholesterol, cholest-5-en-3 beta-ol, the principal sterol of vertebrates and the precursor of many steroids, including bile acids and steroid hormones. It is a component of the plasma membrane lipid bilayer and of plasma lipoproteins and can be found in all animal tissues. |
| kidney development | The process whose specific outcome is the progression of the kidney over time, from its formation to the mature structure. The kidney is an organ that filters the blood and/or excretes the end products of body metabolism in the form of urine. |
| lipoprotein metabolic process | The chemical reactions and pathways involving any conjugated, water-soluble protein in which the covalently attached nonprotein group consists of a lipid or lipids. |
| liver development | The process whose specific outcome is the progression of the liver over time, from its formation to the mature structure. The liver is an exocrine gland which secretes bile and functions in metabolism of protein and carbohydrate and fat, synthesizes substances involved in the clotting of the blood, synthesizes vitamin A, detoxifies poisonous substances, stores glycogen, and breaks down worn-out erythrocytes. |
| low-density lipoprotein particle receptor catabolic process | The chemical reactions and pathways resulting in the breakdown of a low-density lipoprotein particle receptor molecule, a macromolecule that undergoes combination with a hormone, neurotransmitter, drug or intracellular messenger to initiate a change in cell function. |
| lysosomal transport | The directed movement of substances into, out of or within a lysosome. |
| negative regulation of low-density lipoprotein particle clearance | Any process that decreases the rate, frequency or extent of low-density lipoprotein particle clearance. Low-density lipoprotein particle clearance is the process in which a low-density lipoprotein particle is removed from the blood via receptor-mediated endocytosis and its constituent parts degraded. |
| negative regulation of low-density lipoprotein particle receptor binding | Any process that stops, prevents or reduces the frequency, rate or extent of low-density lipoprotein particle receptor binding. |
| negative regulation of low-density lipoprotein receptor activity | Any process that stops, prevents or reduces the frequency, rate or extent of low-density lipoprotein receptor activity. |
| negative regulation of receptor internalization | Any process that stops, prevents, or reduces the frequency, rate or extent of receptor internalization. |
| negative regulation of receptor recycling | Any process that stops, prevents, or reduces the rate of receptor recycling. |
| negative regulation of receptor-mediated endocytosis involved in cholesterol transport | Any process that stops, prevents or reduces the frequency, rate or extent of receptor-mediated endocytosis involved in cholesterol transport. |
| negative regulation of sodium ion transmembrane transporter activity | Any process that stops, prevents or reduces the frequency, rate or extent of sodium ion transmembrane transporter activity. |
| neuron differentiation | The process in which a relatively unspecialized cell acquires specialized features of a neuron. |
| phospholipid metabolic process | The chemical reactions and pathways involving phospholipids, any lipid containing phosphoric acid as a mono- or diester. |
| positive regulation of low-density lipoprotein particle receptor catabolic process | Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the breakdown of low-density lipoprotein particle receptors. |
| positive regulation of neuron apoptotic process | Any process that activates or increases the frequency, rate or extent of cell death of neurons by apoptotic process. |
| positive regulation of receptor internalization | Any process that activates or increases the frequency, rate or extent of receptor internalization. |
| protein autoprocessing | Processing which a protein carries out itself. This involves actions such as the autolytic removal of residues to generate the mature form of the protein. |
| regulation of neuron apoptotic process | Any process that modulates the occurrence or rate of cell death by apoptotic process in neurons. |
| triglyceride metabolic process | The chemical reactions and pathways involving triglyceride, any triester of glycerol. The three fatty acid residues may all be the same or differ in any permutation. Triglycerides are important components of plant oils, animal fats and animal plasma lipoproteins. |
No homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| No homologous proteins | ||||
| 10 | 20 | 30 | 40 | 50 | 60 |
| MGTVSSRRLW | WPLPLLLLLL | LLGPAGARAQ | EDDDGDYEEL | VLALRSEEDG | LADALQHGAT |
| 70 | 80 | 90 | 100 | 110 | 120 |
| ATFHRCAKEP | WRLPGTYVVV | LKEETHRSQP | ERTARRLQAQ | AARRGYLIKL | LHVFHDLLPG |
| 130 | 140 | 150 | 160 | 170 | 180 |
| FLVKMSRDLL | ELALKLPHVD | YIEEDSSVFA | QSIPWNLERI | TPARYRADEY | QPPNGGSLVE |
| 190 | 200 | 210 | 220 | 230 | 240 |
| VYLLDTSIQS | GHREIEGRVM | VTDFGSVPEE | DGTRFHRQAS | KCDSHGTHLA | GVVSGRDAGV |
| 250 | 260 | 270 | 280 | 290 | 300 |
| AKGASLRSLR | VLNCQGKGTV | SSTLIGLEFI | RKSQLVQPVG | PLVVLLPLAG | GYSRVLNAAC |
| 310 | 320 | 330 | 340 | 350 | 360 |
| QRLARAGVVL | VAAAGNFRDD | ACLYSPASAP | EVITVGATNA | QDQPVTLGTL | GTNFGRCVDL |
| 370 | 380 | 390 | 400 | 410 | 420 |
| FAPGEDIIGA | SSDCSTCFVS | RSGTSQAAAH | VAGIAAVMLS | AEPELTLAEL | RQRLIHFSAK |
| 430 | 440 | 450 | 460 | 470 | 480 |
| DVINEAWFPE | DQRVLTPNLV | AALPPSTHGA | GWQLFCRTVW | SAHSGPTRMA | TAMARCAPDE |
| 490 | 500 | 510 | 520 | 530 | 540 |
| ELLSCSSFSS | SGKRRGERIE | AQGGRRVCLA | HNAFGGKGVY | AIARCCLLPQ | ANCSIHTAPP |
| 550 | 560 | 570 | 580 | 590 | 600 |
| AGASMGTRAH | CHQQGHVLTG | CSAHWEVEEL | GTHKPPVLRP | GGQPSQCMGH | SGASTHATCC |
| 610 | 620 | 630 | 640 | 650 | 660 |
| HAPGLECKVK | EHGLPAPQEQ | VTVACEEGWT | LTGCSALPGT | SHILGAYAVD | DTCVVRSQDV |
| 670 | 680 | 690 | |||
| STTGSTSEEA | VAAVAICCRS | RHLAQASQEL | Q |