University:
Kentucky State University
Course:
BIO 408 | Cell Biology
Academic year:

2024
Views:

395

Pages:

38
Author:

behend6abs

The extracellular matrix and cellcell interaction The extracellular matrix (ECM)  The extracellular matrix fills the spaces between cells and binds cells and tissues together.  Composed of different types of proteins and polysaccharides Types: 1. Basal laminae (basements membranes): thin, sheetlike, structure upon which layers of epithelial cells rest  -It supports sheets of epithelial cells -It surrounds muscle cells, adipose cells, and peripheral nerves. 2. Connective tissues (more ECM) - Loose network of proteins and carbohydrates underneath epithelial cell layers where fibroblasts are distributed. - Others: bone, tendon, and cartilage. Matrix structural proteins  Components: 1. Tough fibrous proteins embedded in a gellike polysaccharide ground substance. 2. Adhesion proteins that link components of the matrix both to one another and to attached cells.  Differences in the type and amount of different components make different types of ECM Different ECM composition In bone, the extracellular matrix is hardened by deposition of calcium phosphate crystals. Cartilage contains a high concentration of polysaccharides that form a firm compression-resistant gel. Tendons contain a high proportion of fibrous proteins. Collagens: the major structural protein of the ECM  The most abundant proteins in mammals (25% of the total protein mass).  Long, stiff, triple-stranded helical structure made of three α chains  A basic unit of mature collagen is called tropocollagen.  Rich in glycine (33%), proline (13%), and hydroxyproline (9%)  Sequence is (Gly-Pro- hydroxypro)  Hydroxyl groups stabilize the structure by hydrogen bond formation  Contains hydroxylysine (attachment of polysaccharides)  Crosslinking of chains via lysine and hydroxylysine Types of collagens  30 collagen genes that form >20 different types of collagen that resist tissue stretching.  Types:  Fibril-forming (fibrillary) collagens such as collagen I  Fibril-associated collagens (link collagen fibrils to each other and to ECM components, e.g. collagen types IX and XII link fibrils to one another and to other components in the ECM).  Network-forming collagens, flexible because they are interrupted by non helical short domains e.g. type IV is a constituent of the basal laminae.  Anchoring fibrils associate network-forming collagens to fibrillar collagens  Transmembrane collagens participate in cell matrix interactions Assembly of fibrillar collagens  After secretion, they assemble into collagen fibrils.  Collagen fibrils aggregate into collagen fibers Synthesis of collagen in the ER Procollagen formation Exocytosis ECM tropocollagen By procollagen peptidases Synthesis of collagen  Individual collagen polypeptide chains are synthesized into the endoplasmic reticulum (ER) as pro- chains.  In the ER, selected prolines and lysines are hydroxylated and some of the hydroxylysines are glycosylated.  One  chain combines with two others forming procollagen.  During or following exocytosis, extracellular enzymes, the procollagen peptidases, remove the N-terminal and Cterminal propeptides forming tropocollagen (or simply collagen).  Excision of both propeptides allows the collagen molecules to polymerize into normal fibrils in the extracellular space. Collagen-related diseases Scurvy  Deficiency of vitamin C results in insufficient formation of hydroxyproline and, hence, poor synthesis of collagen, formation of unstable triple helices.  Non-hydroxylated procollagen chains are then degraded within the cell.  Symptoms: skin and gum lesions and weak blood vessels Collagen-related diseases Osteogenesis imperfect (OI) (Brittle-bone disease)  “Osteogenesis imperfecta" = imperfect bone formation  A genetic disorder that cause fragile, soft, brittle, and easily broken bones due to mutations in COL1A1 and COL1A2 genes that interfere with the assembly of type I collagen.  Four types of OI designated as type I through type IV  Type I: the mildest form of the condition  Type II: the most severe form that results in death in utero or shortly after birth  Milder forms generate a severe crippling disease  Autosomal dominant pattern of inheritance  One copy of the altered gene is sufficient to cause the condition Collagen-related diseases Chondrodysplasias  Mutations affecting type II collagen cause chondrodysplasias, characterized by abnormal cartilage, which leads to bone and joint deformities. Collagen-related diseases Ehlers-Danlos syndrome  A heterogeneous group of disorders that affect the skin, bones, blood vessels, and other organs.  The signs and symptoms vary from mild to life-threatening.  All result from defects in collagen synthesis and/or processing.  Mutations in type I, III, or V collagen or in the synthesis of collagen processing enzymes like procollagen N-peptidase, or lysyl hydroxylase Major manifestations: Skin fragility and hyperextensibility Joint hypermobility. Collagen-related diseases Type III EDS  The most clinically important mutations are found in the gene of type III collagen.  Since type III collagen is a major component of arteries, mutations affecting type III collagen result in fragile blood vessels. Hypermobile joints Stretchy skin Symptoms Elastic fibers structure  Abundant in organs to allow them to stretch then return to the original shape, e.g. lungs  The main component of elastic fibers is elastin  Rich in proline and glycine.  Contains hydroxyproline, but no hydroxylysine  Not glycosylated  Elastin has two types of short segments that alternate along the polypeptide chain 1. Hydrophobic segments, which are responsible for the elastic properties of the molecule 2. Alanine- and lysine-rich a-helical segments, which form cross-links between adjacent molecules www.boundless.com Formation of elastic networks Secretion of tropoelastin Assembly into elastic fibers Crosslinking via covalent bonds between lysines Elastic fiber in the arterial walls  Elastin is the dominant ECM protein in arteries.  The normal elasticity of an artery restrains the proliferation of smooth muscle cells.  Abnormal or deficiency of the elastin results in excessive proliferation of smooth muscle cells in the arterial wall and narrowing of the arteries. Microfibrils  An elastin core is covered with a sheath of microfibrils  Microfilrils are composed of a number of distinct glycoproteins, including the large glycoprotein fibrillin, which binds to elastin and is essential for the integrity of elastic fibers.  Present in hair and sperm tail. Marfan's syndrome Due to mutated fibrillin  Rupture of aorta.   Signs and symptoms: A tall, thin build Long arms, legs, fingers, and toes Flexible joints Scoliosis, or curvature of the spine A chest that sinks in or sticks out Crowded teeth Flat feet Emphysema (destructive lung disease)  Due to a dysfunctional alpha-1 antitrypsin leading to increased activity of elastase in lungs  The lysine to-glutamate mutation causes protein misfolding, formation of an aggregate and block of ER export.  Cigarette smoking also inactivates alpha 1-antitrypsin by oxidizing essential methionine residues, decreasing the enzyme activity by a factor of 2000. Matrix polysaccharides  Glycosaminoglycans (GAGs): Polysaccharides of repeated disaccharides in which fibrous proteins are embedded  One is either N-acetylglucosamine or N-acetylgalactosamine  The other is usually acidic (either glucuronic acid or iduronic acid)  highly negatively charged  Modified by sulfate groups, e.g. dermatan sulfate, chondroitin sulfate, keratan sulfate, heparin sulfate.  Exist as proteoglycans   Some are cell surface proteins with either transmembrane domains (syndecans) or GPI anchors (glycipans) interacting with integrins. Hyaluronan: is the only GAG with a single long polysaccharide chain. Aggregan and hyalronan  The major proteoglycan of cartilage  A large proteoglycan consisting of more than 100 chondroitin sulfate chains joined to a core protein.  Multiple aggrecan molecules bind to long chains of hyaluronan that become trapped in the collagen network, forming large complexes in the ECM of cartilage. Perlecan  Proteoglycans bind to matrix proteins forming gel-like networks Heparan sulfate proteoglycan of basal lamina + collagen + laminin Matrix adhesion proteins Fibronectin  They link matrix proteins with one another and to the surfaces of cells.  They interact with collagen and proteoglycans and specify matrix organization and are major binding sites for cell surface receptors such as integrins  Fibronectin: the principal adhesion protein of connective tissues.  A dimeric glycoprotein that is crosslinked into fibrils by s-s bonds.  Binds to collagen and GAGs  Binds to cell surface proteins like integrins linking cells to the ECM Matrix adhesion proteins Laminin   Found in basal laminae  T-shaped heterotrimers with binding sites for cell surface receptors (e.g. integrins), and ECM components, e.g. type IV collagen, and perlecan. Laminins are tightly associated with another adhesion protein, called nidogen, which also binds to type IV collagen, all of which form crosslinked networks in the basal lamina. Cell-matrix interactions Role of integrins  Integrins are a family of transmembrane heterodimers (α and β)  They bind to short sequences present in ECM proteins including collagen, fibronectin, laminin and proteoglycans. Functions of integrins: 1. The major cell surface receptors that attach cells to ECM 2. They anchor the cytoskeleton at focal adhesions and hemidesmosomes. Assembly of focal adhesions Inactive integrins can not bind the matrix. 1. 2. 3. 4. Activation of integrin and binding to ECM Recruitment of additional integrins forming focal complex Development of small integrin clusters called focal complexes Development of focal adhesions by the recruitment of formin, talin, vinculin and α-actinin Cell-cell adhesion is a selective process Cell Adhesion Molecules Family Selectins Integrins Ig superfamily Cadherins Ligands recognized Stable cell junctions Carbohydrates No Extracellular matrix Focal adhesions and hemidesmosomes Members of Ig superfamily No Integrins No Homophilic interactions No Homophilic interactions Adherens junctions and desmosomes Homophilic vs. heterophilic interactions Selectin-mediated interaction between leukocytes and endothelial cells Intercellular adhesion molecules Cadherins adhesion molecules  Selective adhesion between embryonic cells and formation of stable junctions between cells in tissues.  Classic cadherins  E-cadherin: epithelial cells  N-cadherin: neural cells  P-cadherin: placental cells Several subfamilies  Classic, Desmosomal, fat-like and 7-Transmembrane cadherins Adherens junctions Classic cadherins Desmosomes Desmosomal cadherins heterophilic interaction Molecular composition of tight junctions  A network of protein strands that continues around the entire circumference of the cell  Each strand in these networks is composed of transmembrane proteins (claudins, occludin, and JAMs) that bind to similar proteins on adjacent cells, thereby sealing the space between their plasma membranes  These proteins interact with the actin cytoskeleton via zonula occludens protein.  Separate the apical part from the basolateral part of membranes  Prevent the passage of molecules (including ions )between epithelial cells Gap junctions  They provide direct connections between the cytoplasms of adjacent cells as open channels allowing ions and small molecules (<1000 Da) including signaling molecules to diffuse freely between neighboring cells, but preventing the passage of proteins and nucleic acids.  Present in cells like epithelial cells, endothelia cells, cardiac cells and smooth muscle cells Molecular composition of gap junctions  They are made of transmembrane proteins called connexins  Six connexins assemble to form a connexon (a cylinder with an open aqueous pore in its center).  Two connexons on adjacent cells make a gap junction Gap junctions and electrical synapses Specialized connexins in electrical synapse Gap junction diseases Mutations in different types of connexins result in many diseases such as:  Charcot-Marie-Tooth disease (degeneration of peripheral myelinated nerves)  Deafness: inability to rapidly exchange K+  Cataracts: inability to obtain nutrients from the lens epithelial cells  Skin disease

The Extracellular Matrix and Cellcell Interaction

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