Flashcards in M/S BIOLOGY Deck (36):
What does CD44 hyaluronic acid binding protein bind, and what role does it play?
cd44 is a cell surface glycoprotein (ch 1, cd44 gene), expressed on many cell types, that is a receptor for hyaluronic acid as well a collagen, MMPs, and osteopontin. Many post translational modifications alter function. Plays a role in lymphocyte maturation in thymus, splice variants occur in neoplastic markers.
What is the immediate target of Wnt protein and what pathways are stimulated?
Wnt protein (Wingless-related integration site) binds to the Frizzeled family receptor which passes the signal to the protein Disheveled inside the cell.
The canonical pathway then regulates gene expression, the noncanonical planar cell pathway deals with cytoskeleton and noncanonical calcium/Wnt deals with calcium inside the cell.
What is tensin, and what does it link?
Tensin is a 220 kda multi-domain protein that links integrin heterodimers to the plasma membrane, binds to actin filaments, and contains a phosphotyrosine binding protein at the C terminus and a protein tyrosine phosphatase at the N terminus. It is an important component linking the cellular membrane, actin cytoskeleton, and signal transduction.
What is selenoprotein N1?
Selenoprotein contains selenocysteine, and N1 mutations cause muscular dystrophy and in knockout mice results in delayed vertebral fusion.
What is nebulin?
Nebulin is an actin binding protein (600 – 900 kDa) that may act as a ruler for actin length. It also inhibits ATPase activity in a calcium-calmodulin sensitive manner. It's mutated form results in nemaline myopathy.
What is dynamin?
Dynamin is a 96 kDa GTPase responsible for endocytosis, pinching off the vesicle neck.
What is insulin receptor substrate 1?
Insulin receptor substrate 1 (IRS1) binds to the insulin receptor SH domain, gets phosphorylated, then transmit signals from insulin and insulin like growth factor (IGF-1) to intracellular pathways PI3K/Akt, Erk and MAP kinase. Insulin receptor substrate 1 (IRS-1) contains a single PH Domain and PTB (phosphor tyrosine binding) domain.
Deficiency results in mild diabetes but marked growth impairment.
How many types of collagen are there?
There are over 28 types of collagen formed from various combinations of 34 collagen genes. Over 1000 different mutations so far known to cause phenotypic changes.
How many genes participate in metabolic pathways leading to type 1 diabetes, rheumatoid arthritis, and Crohn's disease?
There are at least 149 genes in diabetes type I, 189 in rheumatoid arthritis, and 277 in Crohn's disease that participate in functional pathways that predict disease susceptibility.Use genotypic data from the welcome trust case control Consortium on 14,000 Caucasian UK patients and 3000 controls with 7 diseases; Crohn's, rheumatoid arthritis, type I diabetes, hypertension, type II diabetes, bipolar disorder. Looked at 1415 genes, 20,309 snips within 10 KB of the genes.
What is a reticular cell?
A reticular cell is a type of fibroblast that synthesizes type III collagen producing reticular fibers. These fibers are surrounded by cytoplasm.Reticular cells are found in the spleen, lymph nodes, and may direct B and T cells within the lymphatic tissue.
What is matrix Gla protein?
Matrix Gla protein (MGP) is present usually with osteocalcin and shares the ability to increase production with vitamin D.
What gene produces osteocalcin and accounts for what sort of metabolic changes?
(gene) BGLAP (Gamma-carboxyglutamic acid protein, bone) codes for osteocalcin (100 aa, 11Kda), one of six splice variants of pre-Pro osteocalcin. Osteocalcin is secreted solely by osteoblasts and makes up 2% of bone, binds strongly to calcium and apatite. it acts as a hormone causing insulin production, directing fat cells to induce adiponectin, and increases sensitivity to insulin. It may enhance synthesis of testosterone.
What protein inhibits Wnt signaling?
WIF1 (Wnt inhibitory factor 1) binds Wnt protein with an inhibitory domain. It also has 5 EGF like domains, and is present in all vertebrates.
WIF1 can inhibit Wnt stimulation of fibroblast induced fibrosis, works in DNA damage induced fibrosis and scleroderma.
What are the major motifs on thrombospondin 1 (TSP1)?
thrombospondin1 (TSP1) is a multi-domain 180kD protein that starts with a heparin binding pentraxin domain, then vWC domain (von Willibrand factor type C), then a procollagen homology domain, then uses type I repeats to bind to CD36 and TGFbeta then followed by type 2 repeats with EGF like structure, then then type 3 Ca binding repeats and finally a carboxy-terminal L-lectin domain that binds CD47. CD36 provokes NO production and CD47 with cGMP effects on vascular responses. TSP1 can activate TFG-beta which activates Smads that increase transcription of pro-fibrotic genes.
Thrombospondin has different effects on different cell types which differ in cell membrane receptors-type and density. Macrophages may end up secreting TNF alpha, IL-6 and IL 12 whereas endothelial cells may undergo apoptosis.
What cerebral vascular syndrome is due to a mutation of the notch3 gene?
The CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is usually manifest as migraine headaches progressing to cerebral damage. Mutations of the notch 3 gene are responsible and the protein gene product is found in the involved micro vasculature.
How are migraine headaches and osteoarthritis connected?
Osteoarthritic pain from the neck and back is more common in patients with migraine who also have C-3 allele C3F+ versus C3F-, 44% versus 18% P< 0.0008. Hypertension is more common as well but less significant P< 0.01. C-3 S is the more common allele. ISSN 0333-1024
What is the structure of BMP1?
Bone morphogenic protein 1 contains 202 residues, 10 helices, 11 strands in beta sheets, and ligans for an acetyl group and zinc ion. It is a metalloproteinase rather than a member of the TGFbeta superfamily. It affects cell differentiation through the smad pathways.
BMP-1 may play a role in modulating BMP by proteolysis of BMP antagonists/binding proteins such as noggin and chondrin.
How do BMPs work?
BMPs are released by osteoprogenitors and mesenchymal cells, osteoblasts, bone extracellular matrix, and chondrocytes. They target mesenchymal, osteoprogenitor cells, and osteoblasts to develop into chondrocytes, and osteoblasts.
BMP receptors may phosphorylate each other then cooperate to produce Smads of many types which go on to coordinate gene expression.
What mutations cause hereditary hemorrhagic telangiectasia?
Hereditary hemorrhagic telangiectasia (HHT) may be due to mutations in endoglin, activin receptor like kinase 1 (ALK-1) , Smad4 (MADH4), as well as rarely other genes. Over 600 mutations are known. Most mutations involve TGF-beta superfamily signaling with defective endothelial cell function.
How is a collagen fibril formed?
left-handed alpha helical alpha chains are formed in the rough endoplasmic reticulum where the N-terminal signal peptide is cleaved, proline and lysine residues are hydroxylated and glycosylated. The right-handed triple helix (procollagen) is formed from the propeptide chains, shipped to the golgi apparatus and secreted as procollagen. collagen peptidases trim the procollagen into tropocollagen.Lysyl oxidase then links lysine and hydroxylysine to form aldehyde groups which eventually undergo covalent bonding into a polymer of tropocollagen known as a collagen fiberil.
What inherited diseases are caused by abnormalities in collagen fiber formation-changing procollagen into tropocollagen?
Ehlers-Danlos syndrome is caused by defects among collagen peptidases changing procollagen into tropocollagen
Endoglin is part of what receptor complex and contains what kind of active motifs.
Endoglin is a type I membrane glycoprotein (CD 105, END, HTT1), 668 residues 180 kDa, part of the TGF-beta receptor complex is important in regulating tumor growth and metastases. The extracellular portion binds ligands such as BMP9, and has an RGD (arginine-glycine-aspartic acid) domain for integren adhesion. The intracellular portion has a PTZ binding motif.
What superfamily do activin and inhibin belong?
activin and inhibin are dimeric proteins of the TGFbeta superfamily that use TGF-beta receptors to modify FSH secretion.
By what mechanism does nodal regulate mesoderm formation?
nodal is a member of the TGFbeta superfamily, 347aa, which regulates mesoderm formation in a species-specific manner producing right left symmetry.
How does the beta-catenin cytoplasmic destruction complex function?
In the Beta-catenin cytoplasmic destruction complex, the long adenomatous polyposis coli protein (APC) with multiple binding sites for beta-catenin, and SAMP (ser-ala-met-pro) motifs result in binding Axin proteins through their terminal RGS (regulator of G protein signaling) domains. The C-terminal DIX domains of axin stick to each other forming a large complex. Glycogen synthesis kinase 3 (GSK3) binds to the midportion of axin and phosphorylates beta catenin also on axin thus marking it for destruction. The first phase of Wnt signaling releases disheveled with its own DIX domain, axin is bound, GSK3 cannot function, beta catenin cannot be phosphorylated, accumulates, and eventually travels to the nucleus where the C-terminal region with its transactivator motifs combines with other coactivators to regulate gene transcription.
What transcription factors are active in resting chondrocytes?
Resting chondrocyte depends on the Sox9 and Smad 2/3 to produce type II collagen and aggrecan.
What transcription factors are active in hypertrophic chondrocytes in degenerative joint disease?
Hypertrophic chondrocytes depend on RUNX2, HIF-2alpha, C/EBP beta, Smad 1/5/8 to overcome inhibition from Nfat1, and SirT1.
Cell products include type X collagen, VEGF, osteonectin, IHH, alkaline phosphatase, osteopontin, HtrA1, osteocalcin, and MMP13.
RUNX2-run-related transcription factor 2, associated with osteoblastic differentiation.
HIF-2alpha-hypoxia and visible factor
SirT1- sirtuin 1, silent mating type information regulation 2 homolog, epigenetic modulator
osteonectin-(SPARC gene secreted protein acidic and rich in cysteine) initiates mineralization, crystal formation
HtrA1, G protein coupled serotonin receptor
osteocalcin (bone gamma-carboxyglutamic acid-containing protein BGLAP) bone mineralization.
What cellular precursors and up as chondrocytes?
BMP4 and FGF2 are the major growth factors responsible for mesenchymal stem cells turning into chondrocytes. Chondroblasts are a misnomer
as stem cells become chondrocytes without chondroblastic stage.
What products are secreted by osteoblasts? Is
Osteoblasts secrete collagen as well as growth factors including glycosaminoglycans, osteocalcin, osteonectin, bone sialo protein, osteopontin, and cell attachment factor.
What are the relative strengths of bone in terms of compression, tensile, and shear?
Bone has high compressive strength (170 MPa), poor tensile strength (110 MPa) and very low shear strength stress (50 MPa). It handles pushing forces well but not pulling or torsional.
What does osteocalcin do?
Osteocalcin controls regulation of blood sugar and fat deposition, increases both insulin secretion and sensitivity in addition to boosting the number of insulin-producing cells and reducing stores of fat.
What growth factors are stored in bone?
Growth factors that are stored in bone include insulin like growth factors, transforming growth factors,bone morphogenic proteins
What does noggin do?
noggin (NOG product) is a 232-amino acid protein that binds TGF beta family members such as BMP4, BMP7 preventing stimulation of BMP receptors. Overexpression causes large heads in experimental animals and missense mutations result in abnormal bone fusions.
What the sclerostin do?
sclerostin is a 213-amino acid protein with a secretion signal and 2 N-glycosylation sites with other motifs commonly found in Wnt antagonists. Sclerostin production by osteocytes is inhibited by parathyroid hormone, mechanical loading, prostaglandin E2, oncostatin and leukemia inhibitory factor.
Missense mutations result in excessive bone formation-facial distortion and syndactyly.
The most physically active persons have the lowest sclerostin levels.
Romosozumab-monoclonal against sclerostin is effective against osteoporosis (Amgen 2017).
What are chimeric antigen receptors and how do they work in cancer chemotherapy?
Chimeric antigen receptors are transmembrane proteins with immunoglobulin based antigen recognition sequences then a transmembrane sequence then cell activating sequences CD3-zeta with 3 ITAMS, or other cell activating sequences CD28, PI3K, TRAF2, 4-1BB,OX40. Killer T cells, Natural killer cells, macrophages thus armed can recognize and kill cancer cells.