YWTD repeat

Last updated
LDL receptor repeat class B
Identifiers
SymbolLdl_recept_b
Pfam PF00058
InterPro IPR000033

YWTD repeats are four-stranded beta-propeller repeats found in low-density lipoprotein receptors (LDLR). The six YWTD repeats together fold into a six-bladed beta-propeller (InterPro : IPR011042 ). Each blade of the propeller consists of four antiparallel beta-strands; the innermost strand of each blade is labeled 1 and the outermost strand, 4. The sequence repeats are offset with respect to the blades of the propeller, such that any given 40-residue YWTD repeat spans strands 24 of one propeller blade and strand 1 of the subsequent blade. This offset ensures circularization of the propeller because the last strand of the final sequence repeat acts as an innermost strand 1 of the blade that harbors strands 24 from the first sequence repeat. The repeat is found in a variety of proteins that include, vitellogenin receptor from Drosophila melanogaster , low-density lipoprotein (LDL) receptor, [1] preproepidermal growth factor, and nidogen (entactin). [2]

InterPro is a database of protein families, domains and functional sites in which identifiable features found in known proteins can be applied to new protein sequences in order to functionally characterise them.

<i>Drosophila melanogaster</i> Species of fruit fly

Drosophila melanogaster is a species of fly in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting with Charles W. Woodworth's proposal of the use of this species as a model organism, D. melanogaster continues to be widely used for biological research in genetics, physiology, microbial pathogenesis, and life history evolution. As of 2017, eight Nobel prizes had been awarded for research using Drosophila.

The LDLR regulates cholesterol homeostasis in mammalian cells. LDLR binds cholesterol-carrying LDL, associates with clathrin-coated pits, and is internalized into acidic endosomes where it separates from its ligand. The ligand is degraded in lysosomes, while the receptor returns to the cell surface. [3] The LDLR has several domains. The ligand-binding domain contains seven LDL receptor class A repeats, each with three disulphide bonds and a coordinated Ca2+ ion. The second conserved region contains two EGF repeats, followed by six YWTD or LDL receptor class B repeats and another EGF repeat. [4] This conserved region is critical for ligand release and recycling of the receptor. [5]

Cholesterol sterol biosynthesized by all animal cells which is an essential structural component of all animal cell membranes

Cholesterol is an organic molecule. It is a sterol, a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membranes.

Endosome A vacuole to which materials ingested by endocytosis are delivered.

In cell biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway originating from the trans Golgi membrane. Molecules or ligands internalized from the plasma membrane can follow this pathway all the way to lysosomes for degradation, or they can be recycled back to the plasma membrane. Molecules are also transported to endosomes from the trans-Golgi network and either continue to lysosomes or recycle back to the Golgi. Endosomes can be classified as early, sorting, or late depending on their stage post internalization. Endosomes represent a major sorting compartment of the endomembrane system in cells. In HeLa cells, endosomes are approximately 500 nm in diameter when fully mature.

Lysosome small lytic vacuole with cell cycle-independent morphology, found in most animal cells; contains a variety of hydrolases, most of which have their maximal activities in the pH range 5-6

A lysosome is a membrane-bound organelle found in many animal cells and most plant cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane proteins, and its lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach. Besides degradation of polymers, the lysosome is involved in various cell processes, including secretion, plasma membrane repair, cell signaling, and energy metabolism.

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Low-density lipoprotein one of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein which transport all fat molecules around the body in the extracellular water. These groups, from least dense, compared to surrounding water to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein and high-density lipoprotein (HDL). LDL delivers fat molecules to the cells and can drive the progression of atherosclerosis if they become oxidized within the walls of arteries.

Lipoprotein biochemical assembly whose purpose is to transport hydrophobic lipid (a.k.a. fat) molecules in water, as in blood or extracellular fluid

A lipoprotein is a biochemical assembly whose primary purpose is to transport hydrophobic lipid molecules in water, as in blood or extracellular fluid. They have a single-layer phospholipid and cholesterol outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions of each molecule oriented inwards toward the lipids molecules within the particles. Apolipoproteins are embedded in the membrane, both stabilising the complex and giving it functional identity determining its fate. Thus the complex serves to emulsify the fats. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins. Examples include the plasma lipoprotein particles classified as HDL, LDL, IDL, VLDL and ULDL lipoproteins, according to density / size, compared with the surrounding plasma water. These complex protein capsules enable fats to be carried in all extracellular water, including the blood stream, subgroups of which are primary drivers / modulators of atherosclerosis, the transmembrane proteins of mitochondrion, chloroplast, and bacterial lipoproteins. Proteolipids are a different kind of protein-lipid combination that are insoluble in water. Proteolipids are abundant in brain tissue, and are also present in many other animal and plant tissues.

Intermediate-density lipoproteins (IDLs) belong to the lipoprotein particle family and are formed from the degradation of very low-density lipoproteins as well as high-density lipoproteins. IDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream. Each native IDL particle consists of protein that encircles various lipids, enabling, as a water-soluble particle, these lipids to travel in the aqueous blood environment as part of the fat transport system within the body. Their size is, in general, 25 to 35 nm in diameter, and they contain primarily a range of triacylglycerols and cholesterol esters. They are cleared from the plasma into the liver by receptor-mediated endocytosis, or further degraded by hepatic lipase to form LDL particles.

Apolipoprotein

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Michael Stuart Brown American geneticist and Nobel laureate

Michael Stuart Brown ForMemRS is an American geneticist and Nobel laureate. He was awarded the Nobel Prize in Physiology or Medicine with Joseph L. Goldstein in 1985 for describing the regulation of cholesterol metabolism.

LDL receptor protein-coding gene in the species Homo sapiens

The Low-Density Lipoprotein (LDL) Receptor (LDL-R) is a mosaic protein of 839 amino acids that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100, which is embedded in the outer phospholipid layer of LDL particles. The receptor also recognizes the apoE protein found in chylomicron remnants and VLDL remnants (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.

Beta-propeller

In structural biology, a beta-propeller is a type of all-β protein architecture characterized by 4 to 8 highly symmetrical blade-shaped beta sheets arranged toroidally around a central axis. Together the beta-sheets form a funnel-like active site.

Low-density lipoprotein receptor gene family

The low-density lipoprotein receptor gene family codes for a class of structurally related cell surface receptors that fulfill diverse biological functions in different organs, tissues, and cell types. The role that is most commonly associated with this evolutionarily ancient family is cholesterol homeostasis. In humans, excess cholesterol in the blood is captured by low-density lipoprotein (LDL) and removed by the liver via endocytosis of the LDL receptor. Recent evidence indicates that the members of the LDL receptor gene family are active in the cell signalling pathways between specialized cells in many, if not all, multicellular organisms.

VLDL receptor protein-coding gene in the species Homo sapiens

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Foam cell fat-laden M2 macrophages seen in atherosclerosis

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Leucine-rich repeat protein structural motif that forms an α/β horseshoe fold

A leucine-rich repeat (LRR) is a protein structural motif that forms an α/β horseshoe fold. It is composed of repeating 20–30 amino acid stretches that are unusually rich in the hydrophobic amino acid leucine. These tandem repeats commonly fold together to form a solenoid protein domain, termed leucine-rich repeat domain. Typically, each repeat unit has beta strand-turn-alpha helix structure, and the assembled domain, composed of many such repeats, has a horseshoe shape with an interior parallel beta sheet and an exterior array of helices. One face of the beta sheet and one side of the helix array are exposed to solvent and are therefore dominated by hydrophilic residues. The region between the helices and sheets is the protein's hydrophobic core and is tightly sterically packed with leucine residues.

Familial hypercholesterolemia familial hyperlipidemia characterized by very high levels of low-density lipoprotein (LDL) and early cardiovascular disease

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein, in the blood and early cardiovascular disease. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

LDL-receptor-related protein-associated protein protein-coding gene in the species Homo sapiens

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.

Sterol regulatory element-binding protein 1 protein-coding gene in the species Homo sapiens

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OLR1 protein-coding gene in the species Homo sapiens

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LRP1 protein-coding gene in the species Homo sapiens

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.

PCSK9 protein-coding gene in the species Homo sapiens

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

EGF-like domain

The EGF-like domain is an evolutionary conserved protein domain, which derives its name from the epidermal growth factor where it was first described. It comprises about 30 to 40 amino-acid residues and has been found in a large number of mostly animal proteins. Most occurrences of the EGF-like domain are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted. An exception to this is the prostaglandin-endoperoxide synthase. The EGF-like domain includes 6 cysteine residues which in the epidermal growth factor have been shown to form 3 disulfide bonds. The structures of 4-disulfide EGF-domains have been solved from the laminin and integrin proteins. The main structure of EGF-like domains is a two-stranded β-sheet followed by a loop to a short C-terminal, two-stranded β-sheet. These two β-sheets are usually denoted as the major (N-terminal) and minor (C-terminal) sheets. EGF-like domains frequently occur in numerous tandem copies in proteins: these repeats typically fold together to form a single, linear solenoid domain block as a functional unit.

LRP6 protein-coding gene in the species Homo sapiens

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.

References

  1. Russell DW, Schneider WJ, Yamamoto T, Brown MS, Goldstein JL, Davis CG, Casey ML (1984). "The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA". Cell. 39 (1): 27–38. doi:10.1016/0092-8674(84)90188-0. PMID   6091915.
  2. Eck MJ, Springer TA, Blacklow SC, Takagi J, Jeon H, Meng W (2001). "Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair". Nat. Struct. Biol. 8 (6): 499–504. doi:10.1038/88556. PMID   11373616.
  3. Brown MS, Goldstein JL (1986). "A receptor-mediated pathway for cholesterol homeostasis". Science. 232 (4746): 34–47. doi:10.1126/science.3513311. PMID   3513311.
  4. Springer TA (1998). "An extracellular beta-propeller module predicted in lipoprotein and scavenger receptors, tyrosine kinases, epidermal growth factor precursor, and extracellular matrix components". J. Mol. Biol. 283 (4): 837–862. doi:10.1006/jmbi.1998.2115. PMID   9790844.
  5. Russell DW, Brown MS, Goldstein JL, Davis CG, Sudhof TC, Anderson RG (1987). "Acid-dependent ligand dissociation and recycling of LDL receptor mediated by growth factor homology region". Nature. 326 (6115): 760–765. doi:10.1038/326760a0. PMID   3494949.
This article incorporates text from the public domain Pfam and InterPro: IPR000033