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Intermediate Filaments.Pdf MEDICAL CELL BIOLOGY INTERMEDIATE FILAMENTS October 2, 2003 Thomas J. Schmidt, Ph.D. Department of Physiology and Biophysics 5-610 BSB, 335-7847 Reading Assignment: Molecular Biology of the Cell (4th ed..), 2001, by B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter; Chapter 16, pp. 923-929 Key Concepts: 1. Intermediate filaments are strong polymers of fibrous polypeptides that resist stretch and play a structural function. 2. The four major classes of intermediate filaments include: keratin filaments, neurofilaments, vimentin-containing filaments and nuclear lamins. 3. The first three classes of intermediate filaments are expressed in a tissue-specific manner. 4. The morphology of these elongated molecules includes: a subunit- specific NH2-terminus (head) of variable size; a homologous central α-helical region (rod domain); and a subunit-specific COOH- terminus (tail). 5. Intermediate filaments resist mechanical force, are a major component of the protective outer layer of skin cells and strengthen epithelia undergoing shape changes during morphogenesis. Key Terms: intermediate filaments glial fibrillary acidic protein keratin desmin hemidesmosomes peripherin desmosomes nuclear lamins neurofilaments epidermolysis bullosa simplex amyotrophic lateral sclerosis vimentin Medical Cell Biology Intermediate Filaments 1 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 Medical Cell Biology Intermediate Filaments 2 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 Clinical Correlation: situation Mary Smith, a 1 week-old female infant, was brought to the Pediatric Newborn Clinic. The infant was born at term and seemed normal at birth. Birth weight was 7 lbs. 4 oz. The pregnancy was normal. The mother was concerned because her infant had numerous skin blisters, predominantly in areas where her diaper had contact with her skin, but also elsewhere on her body. Discussions with the mother did not prove any evidence of child abuse. Medical Cell Biology Intermediate Filaments 3 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 Lecture Outline: II. Intermediate Filaments A. Definition - strong polymers of fibrous polypeptides that resist stretch and play a structural (tension-bearing) function B. Found in most, but not all cell types C. Most important function is to provide mechanical support for plasma membrane where it comes into contact with other cells or extracellular matrix. D. Reinforce cells and organization of cells into tissues E. Form a tight weave around the nucleus and then spread toward plasma membrane F. Form a tightly woven basketwork, the nuclear lamina, inside the nuclear envelope G. Characteristics 1. intermediate diameter (10nm) 2. subunits are fibrous proteins and almost all are incorporated into stable intermediate filaments 3. ATP or GTP hydrolysis is not requied for intermediate filament polymerization 4. no polarity of intermediate filaments 5. insoluble fiber system 6. tissue-specific forms of intermediate filaments contain different subunits (Fig. 16-13, Table 16-1) Medical Cell Biology Intermediate Filaments 4 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 Medical Cell Biology Intermediate Filaments 5 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 Medical Cell Biology Intermediate Filaments 6 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 a. keratin filaments (most diverse family of subunits) are found in epithelial cells i. type I (acidic) ii. type II (neutral/basic) iii. heteropolymers formed from 1:1 ratio of type I and type II polypeptides iv. hard keratins - nails, hair etc. v. each epithelial cell type expresses a characteristic heteropolymer of type I and type II keratins – clinically useful in diagnosis of epiththelial cancers vi. role of ketarin filaments in normal cells – desmosomes (bond neighboring cells) and hemidesmosomes (anchor cells to underlying basal lamina Medical Cell Biology Intermediate Filaments 7 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 • desmoglein (major protein in skin desmosomes) – autoantibodies disrupt adhesion between cells causing blistering of skin and mucous membranes • demoplakin – recessive mutations in gene causes skin disorder and cardiac arrythmias that can lead to sudden cardiac death b. neurofilaments - found in neurons and form cytoskeleton of axons and dendrites i. heteropolymers of three different neurofilament polypeptides ii. number of neurofilaments determines diameter of axon- speed of impulse iii. neurodegenerative disease – amyotrophic lateral sclerosis (ALS, Lou Gehrig’s Disease) • associated with an accumulation and abnormal assembly of neurofilaments in motor neuron cell bodies and axons • degeneration of axons leads to muscle weakness and atrophy c. filaments composed of vimentin-like proteins i. vimentin - present in many cells of mesodermal origin including fibroblasts, endothelial cells and white blood cells. ii. Frequently associated with microtubules iii. glial fibrillary acidic protein - glial cells iv. desmin - muscle cells (stabilizes sarcomeres) • mutations prevent polymerization and formation of filamentous network • slowly progressive respiratory insufficiency can lead to disability and death Medical Cell Biology Intermediate Filaments 8 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 v. peripherin - neurons d. nuclear lamins - form two- dimensional sheet like lattice of intermediate filaments (nuclear lamina) on inner surface of nuclear envelope i. the nuclear lamina network disassembles at start of mitosis and then reassembles at the end of mitosis ii. mediated by phosphorylation/dephosphorylation of serine residues on nuclear lamin polypeptides Medical Cell Biology Intermediate Filaments 9 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 G. Morphology of elongated fibrous intermediate filament molecules (Fig. 16-16) 1. subunit-specific NH2-terminus (head) of variable size 2. homologous central α-helical region (rod domain) contains long tandem repeats of distinctive amino acid sequence called “heptad repeat” 3. subunit-specific COOH-terminus (tail) of variable size Medical Cell Biology Intermediate Filaments 10 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 4. variable regions facilitate attachment to other cytoskeletal structures a. plectin makes bundles of vimentin b. plectin links intermediate filaments to microtubules and actin filament bundles c. plectin attaches intermediate filaments to plasma membrane d. mutations in plectin gene cause a devastating human disease 5. assembly of intermediate filament - bundles of keratin filaments held together by filaggrin 6. in most cells intermediate filament protein molecules are in fully polymerized state, with very little free tetramer. H. Functions 1. some keratins strengthen epithelia undergoing shape changes during morphogenesis 2. some keratins are very abundant in the tough protective outer layer of skin cells 3. resist mechanical stress as demonstrated by blistering of skin caused by mutant keratin gene (example: epidermolysis bullosa simplex) (Fig. 16-19) Medical Cell Biology Intermediate Filaments 11 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 Medical Cell Biology Intermediate Filaments 12 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 Reprints on Reserve at Hardin Library: 1. Fuchs, Elaine and Don Cleveland. 1998. A structural scaffolding of intermediate filaments in Health and Disease Science. 279:514-519. 2. Goldmann, Robert, Ying-Hao Chou, Veena Prahald, and Min Yoon. 1999. Intermediate Filaments: dynamic processes regulating their assembly, motility, and interactions with other cytoskeletal systems. FASEB. 13(Suppl.):S261-S265. 3. Fuchs, Elaine and Pierre A. Coulombe. 1992. Of Mice and Men: Genetic Skin Disease of Keratin. Cell. 69:899-902. 4. Osborn, Mary and Klaus Weber. 1983. Tumor Diagnosis by Intermediate Filament Typing: A Novel Tool for Surgical Pathology. Laboratory Investigation. 48(4):372- 394. 5. Metzger, A.R., Rosenheck, S., Meiner, V. and Chajek-Shaul T. 2003. A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J. Am. Coll. Cardiol. 42:319-327. 6. Dagvadorj, A., et al. 2003. Respiratory insufficiency in desminopathy patients caused by introduction of praline rich residues in desmin c-terminal alpha-helical segment. Muscle Nerve 27:669-675. Medical Cell Biology Intermediate Filaments 13 Thomas J. Schmidt, Ph.D. Email: [email protected] October 2, 2003 .
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