A mosaic protein is a protein that is made up of different protein domains , giving the protein multiple functions. These proteins have quaternary structures, as they are made up of multiple tertiary structured protein domains. Protein domains can combine to form different types of proteins, creating a diversity of proteins. These domains are spread throughout the genome because they are mobile, which is why some domains can be found in a variety of proteins, even though they are seemingly unrelated. This also allows the domains to fold independently, and so they don't become deformed and unfolded in a new environment.
35-569: 1AJJ , 1D2J , 1F5Y , 1HJ7 , 1HZ8 , 1I0U , 1IJQ , 1LDL , 1LDR , 1N7D , 1XFE , 2FCW , 2KRI , 2LGP , 2W2M , 2W2N , 2W2O , 2W2P , 2W2Q , 3BPS , 3GCW , 3GCX , 3M0C , 3SO6 , 2M7P , 2MG9 , 3P5B , 3P5C , 4NE9 3949 16835 ENSG00000130164 ENSMUSG00000032193 P01130 P35951 NM_001195803 NM_001252658 NM_001252659 NM_010700 NP_000518 NP_001182727 NP_001182728 NP_001182729 NP_001182732 NP_001239587 NP_001239588 NP_034830 The low-density lipoprotein receptor ( LDL-R )
70-427: A class A repeat or LDL-A , contains roughly 40 amino acids, including 6 cysteine residues that form disulfide bonds within the repeat. Additionally, each repeat has highly conserved acidic residues which it uses to coordinate a single calcium ion in an octahedral lattice. Both the disulfide bonds and calcium coordination are necessary for the structural integrity of the domain during the receptor's repeated trips to
105-851: A high clinical relevance in blood lipids. A multi-locus genetic risk score study based on a combination of 27 loci, including the LDLR gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmö Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). Click on genes, proteins and metabolites below to link to respective articles. Mosaic protein Whereas many proteins are encoded by
140-429: A single gene, many others get peptide chains from several genes; it is the nature of mosaic proteins that they are always polygenic. All proteins are transcribed and produced from blueprints in the cell, called genes . Mosaic proteins can be made when two adjacent genes are transcribed together and are therefore made into the same protein. This can benefit the protein because it makes the protein more stable and gives
175-409: A specific enzyme aldosterone synthase (also known as CYP11B2 ). Aldosterone is largely responsible for the long-term regulation of blood pressure . Aldosterone 's effects are on the distal convoluted tubule and collecting duct of the kidney where it causes increased reabsorption of sodium and increased excretion of both potassium (by principal cells) and hydrogen ions (by intercalated cells of
210-542: 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 that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnants—i.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which
245-433: Is also stimulated by adrenocorticotropic hormone (ACTH). The cells of the zona glomerulosa do not express 11β-hydroxylase and 17α-hydroxylase . This is the reason zona glomerulosa cannot synthesize cortisol , corticosterone or sex hormones ( androgens ). The expression of neuron-specific proteins in the zona glomerulosa cells of human adrenocortical tissues has been predicted and reported by several authors and it
280-755: Is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19 . It belongs to the low density lipoprotein receptor gene family . It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue. Michael S. Brown and Joseph L. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine for their identification of LDL-R and its relation to cholesterol metabolism and familial hypercholesterolemia . Disruption of LDL-R can lead to higher LDL-cholesterol as well as increasing
315-464: Is produced in the adrenocortical zona glomerulosa by the action of the enzyme aldosterone synthase (also known as CYP11B2 ). Aldosterone is largely responsible for the long-term regulation of blood pressure . Aldosterone effects on the distal convoluted tubule and collecting duct of the kidney where it causes increased reabsorption of sodium and increased excretion of both potassium (by principal cells) and hydrogen ions (by intercalated cells of
350-510: Is the ACTH that is released from the anterior pituitary . It has been shown that the steroidogenic capacity of the zona fasciculata increases during illness in infants. The inner most cortical layer, the zona reticularis produces adrenal androgens, as well as small amounts of estrogens and some glucocorticoids. The zona reticularis has more of the cofactors required for the 17,20-lyase activity of 17α-hydroxylase than zona fasciculata. Therefore,
385-399: The adrenal gland . It is divided into three separate zones: zona glomerulosa , zona fasciculata and zona reticularis . Each zone is responsible for producing specific hormones. It is also a secondary site of androgen synthesis. The adrenal cortex comprises three main zones, or layers that are regulated by distinct hormones as noted below. This anatomic zonation can be appreciated at
SECTION 10
#1732883553061420-496: The endocytosis of cholesterol-rich LDL and thus maintains the plasma level of LDL. This occurs in all nucleated cells, but mainly in the liver which removes ~70% of LDL from the circulation. LDL receptors are clustered in clathrin -coated pits, and coated pits pinch off from the surface to form coated endocytic vesicles that carry LDL into the cell. After internalization , the receptors dissociate from their ligands when they are exposed to lower pH in endosomes . After dissociation,
455-463: The endoplasmic reticulum and are modified by the Golgi apparatus before travelling in vesicles to the cell surface. In humans, LDL is directly involved in the development of atherosclerosis , which is the process responsible for the majority of cardiovascular diseases , due to accumulation of LDL-cholesterol in the blood . Hyperthyroidism may be associated with reduced cholesterol via upregulation of
490-440: The zona fasciculata . Glucocorticoids are steroid hormones that are necessary for life. They play a role in numerous physiological responses including; metabolism, immune response, mood, cognitive functions, cardiovascular function, and reproduction. Glucocorticoids are also widely prescribed as medication to treat numerous conditions such as autoimmune diseases and lymphoproliferative diseases. The main glucocorticoid in humans
525-746: The EGF precursor gene. There are three "growth factor" repeats; A, B and C. A and B are closely linked while C is separated by the YWTD repeat region, which adopts a beta-propeller conformation (LDL-R class B domain ). It is thought that this region is responsible for the pH-dependent conformational shift that causes bound LDL to be released in the endosome . A third domain of the protein is rich in O-linked oligosaccharides but appears to show little function. Knockout experiments have confirmed that no significant loss of activity occurs without this domain. It has been speculated that
560-487: The LDL receptor, and hypothyroidism with the converse. A vast number of studies have described the relevance of LDL receptors in the pathophysiology of atherosclerosis, metabolic syndrome, and steatohepatitis. Previously, rare mutations in LDL-genes have been shown to contribute to myocardial infarction risk in individual families, whereas common variants at more than 45 loci have been associated with myocardial infarction risk in
595-414: The band 19p13.2 and is split into 18 exons . Exon 1 contains a signal sequence that localises the receptor to the endoplasmic reticulum for transport to the cell surface. Beyond this, exons 2-6 code the ligand binding region; 7-14 code the epidermal growth factor (EGF) domain; 15 codes the oligosaccharide rich region; 16 (and some of 17) code the membrane spanning region; and 18 (with the rest of 17) code
630-414: The body that stimulate the body to produce antibodies specific to that germ. This ensures that the body will build an immunity , and that next time the germ is introduced, it will be more equipped to fight it off. Mosaic proteins of the germs can be designed in order to maximize antibody production and quality. Adrenal cortex The adrenal cortex is the outer region and also the largest part of
665-455: The collecting duct). Sodium retention is also a response of the distal colon, and sweat glands to aldosterone receptor stimulation. Although sustained production of aldosterone requires persistent calcium entry through low-voltage activated Ca channels , isolated zona glomerulosa cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca channels entry. Glucocorticoids are produced mainly in
700-445: The collecting duct). Sodium retention is also a response of the distal colon, and sweat glands to aldosterone receptor stimulation. Although sustained production of aldosterone requires persistent calcium entry through low-voltage activated Ca channels , isolated zona glomerulosa cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permit Ca channels entry. The secretion of aldosterone
735-446: The cytosolic domain. This gene produces 6 isoforms through alternative splicing. This protein belongs to the LDLR family and is made up of a number of functionally distinct domains , including 3 EGF-like domains, 7 LDL-R class A domains, and 6 LDL-R class B repeats. The N-terminal domain of the LDL receptor, which is responsible for ligand binding, is composed of seven sequence repeats (~50% identical). Each repeat, referred to as
SECTION 20
#1732883553061770-472: The cytosolic sequence have been found in other lipoprotein receptors, as well as in more distant receptor relatives. Loss-of-function mutations in the gene encoding the LDL receptor are known to cause familial hypercholesterolaemia. There are 5 broad classes of mutation of the LDL receptor: Gain-of-function mutations decrease LDL levels and are a target of research to develop a gene therapy to treat refractory hypercholesterolemia. LDL receptor mediates
805-463: The domain may have ancestrally acted as a spacer to push the receptor beyond the extracellular matrix . The single transmembrane domain of 22 (mostly) non-polar residues crosses the plasma membrane in a single alpha helix . The cytosolic C-terminal domain contains ~50 amino acids, including a signal sequence important for localizing the receptors to clathrin-coated pits and for triggering receptor-mediated endocytosis after binding. Portions of
840-512: The glomerulosa and reticularis, the cells of the zona fasciculata synthesize and secrete glucocorticoids (such as 11-deoxycorticosterone , corticosterone , and cortisol ), as well as small amounts of adrenal androgens and estrogens . The zona fasciculata has more 3β-hydroxysteroid dehydrogenase activity than the zona reticularis. Therefore, the zona fasciculata makes more 11-deoxycorticosterone , corticosterone , and cortisol . The major hormone that stimulates cortisol secretion in humans
875-456: The highly acidic interior of the endosome . The exact mechanism of interaction between the class A repeats and ligand (LDL) is unknown, but it is thought that the repeats act as "grabbers" to hold the LDL. Binding of ApoB requires repeats 2-7 while binding ApoE requires only repeat 5 (thought to be the ancestral repeat). Next to the ligand binding domain is an EGF precursor homology domain (EGFP domain). This shows approximately 30% homology with
910-411: The major source of cholesterol appears to be cholesterol that is taken up with circulating lipoproteins. The steps up to this point occur in many steroid -producing tissues. Subsequent steps to generate aldosterone and cortisol, however, primarily occur in the adrenal cortex: The adrenal cortex produces a number of different corticosteroid hormones . The primary mineralocorticoid , aldosterone ,
945-411: The microscopic level, where each zone can be recognized and distinguished from one another based on structural and anatomic characteristics. The outermost layer, the zona glomerulosa is the main site for the production of aldosterone , a mineralocorticoid . The synthesis and secretion of aldosterone are mainly regulated by the renin–angiotensin–aldosterone system . The zona glomerulosa cells express
980-417: The overall functions of different proteins. For example, SpCRL and SpCRS proteins in sea urchins have a variety of functional domains that are also found within other proteins in the animal. By making comparisons, scientists can understand the complex roles these proteins play. Also, scientists are using the concept of mosaic proteins to improve vaccine function. Vaccines are injections of weak germ cells into
1015-553: The population. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III. Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk. Overall, LDLR has
1050-485: The primary mode of entry for the Vesicular stomatitis virus in mice and humans. In addition, LDLR modulation is associated with early atherosclerosis-related lymphatic dysfunction. Synthesis of receptors in the cell is regulated by the level of free intracellular cholesterol; if it is in excess for the needs of the cell then the transcription of the receptor gene will be inhibited. LDL receptors are translated by ribosomes on
1085-514: The protein a more complex function. For example, if the protein is an enzyme , it will be able to act more efficiently with its substrates . Additionally, these proteins are most utilized outside of the cell membrane or on the outer side of membrane proteins. This suggests that these multifunctional proteins played a part in the development of multicellular organisms . There are many studies comparing different mosaic proteins and their functional domains, trying to understand protein families and
LDL receptor - Misplaced Pages Continue
1120-463: The receptor folds back on itself to obtain a closed conformation and recycles to the cell surface. The rapid recycling of LDL receptors provides an efficient mechanism for delivery of cholesterol to cells. It was also reported that by association with lipoprotein in the blood, viruses such as hepatitis C virus , Flaviviridae viruses and bovine viral diarrheal virus could enter cells indirectly via LDLR-mediated endocytosis. LDLR has been identified as
1155-549: The risk of related diseases. Individuals with disruptive mutations (defined as nonsense , splice site , or indel frameshift ) in LDLR have an average LDL-cholesterol of 279 mg/dL , compared with 135 mg/dL for individuals with neither disruptive nor deleterious mutations. Disruptive mutations were 13 times more common in individuals with early-onset myocardial infarction or coronary artery disease than in individuals without either disease. The LDLR gene resides on chromosome 19 at
1190-405: The zona reticularis makes more androgens , mainly dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione (the precursor to testosterone ) in humans. The secretion of DHEAS is also stimulated by ACTH. The precursor of steroids synthesized in the adrenal cortex is cholesterol that is stored in vesicles. Cholesterol can be synthesized de novo in the adrenal cortex. Yet,
1225-452: Was suggested that the expression of proteins like the neuronal cell adhesion molecule (NCAM) in the cells of the zona glomerulosa reflects the regenerative feature of these cells, which would lose NCAM immunoreactivity after moving to the zona fasciculata . However, together with other data on neuroendocrine properties of zona glomerulosa cells, NCAM expression may reflect a neuroendocrine differentiation of these cells. Situated between
#60939