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ANAT 262 (65)
Lecture

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Department
Anatomy & Cell Biology
Course
ANAT 262
Professor
John Presley
Semester
Winter

Description
Intermediate Filaments: Intermediate filaments derive their name from the fact that their diameter (10nm) is intermediate to AF and MTs - IFs can be found in the nucleus and cytoplasm - nuclear IFs are composed of lamins and form the 2D meshwork underlying the nuclear envelope - non-polar, static structures which give cells rigidity, very stable (long turnover time) - no motor proteins (not polar), primarily give structure (not much happens with them over time - not as dynamic as MT or AF) IFPs can be divided into 6 classes: - types I (acidic) and II (basic) - keratins are co-expressed in all types of epithelial cells (these are the largest classes) - keratin filaments (found in the skin) are heteropolymers containing equal amounts of type I and type II keratin - this large family of proteins are involved in forming hair, nails, and toughening of the skin - also found in desmosomes (strongest cellular junction) - type III IFPs are expressed in different cell types - vimemtin is expressed in mesenchymal cells and also expressed in a variety of tissue during early stages of development - generally form homopolymeric IFs - bind with themselves to make an IF - type IV (neurofilaments) are mostly expressed in neurons - type V are the nuclear lamins - type VI - nestin - transiently expressed during differentiation (found in development of an embryo) The molecular weights of IFPs differ greatly (40-220 kDa) yet these proteins as- semble to give the typical IF with a diameter of 10 nm - the reason for this ability of such a heterogenous class of proteins to form filament of similar morphology is because they contain a domain that is highly conserved in size (310 AA) and in sequence - the alpha helical rod domain - always give bundle that is 10 nm in diameter - the AA sequence of the rod domain has a characteristic heptad repeat pattern (ran- dom repeats of 7 AA in which the 1st (a) and 4th (d) are hydrophobic) - 1st and 4th amino acid will stick out - the amino terminal (head) and carboxyl terminal (tail) are variable in size and se- quence and are generally responsible for the specific biochemical properties of the dif- ferent IFs made up of a variety of proteins yet the diameter is always 10 nm in diameter - this is because of the heptad AA repeat pattern The first step involves parallel association of two subunits via their alpha helical domains by coiled coiling = dimer formation (self dimerizes) - heads in same directions, tails will wrap due to the repeat - next step in assembly involves the association of two coiled coil dimers in anti- parallel fashion to form a tetramer (this can be looked upon as the basic building blocks of IF) - staggered tetramer (head to tail) - because of the antiparallel orientation the two ends of the tetramer look identical - therefore not polar - subsequent steps involve linear and lateral associations between tetramers to eventu- ally form an IF - the final IF contains 32 polypeptides in cross section - 8 tetramers in a rope IF proteins have huge differences in size...but the polypeptides coil around each other to make a coiled-coil dimer which bind to another dimer to make a tetramer which can form 8 tetramers together to make a rope - this IF is always 10 nm in diameter IF proteins differ from AFs and MTs in 5 important ways: 1) IFPs are not as highly conserved as actin and tubulin - variety of IFPs in size and what they do 2) IFPs are elongated, flexible molecules; actin/tubulin are globular proteins 3) IFPs polymerization does not involve NTP hydrolysis - IFPs do not need energy 4) actin and tubulin are expressed in all eukaryotic cells at least in some phase of development whereas IFP expression is tissue specific 5) IFPs are non-polar Cell Motility: actin polymerization at the leading edge causes cell motility Cell motility pays a central role in a variety of biological processes - in embryology, cellular migrations are a recurring theme in important morphological processes ranging from gastrulation to nervous system development - wound healing involves the essential migration of fibroblasts and vascular endothelial cells - in metastasis, tumor cells migrate from the initial tumor mass into the circulation sys- tem which they subsequently leave to migrate to a new site although much is known about the individual process of underlying cell migration, there is still much to learn about how the various stages of are coordinated spatial and tempo- rally Assembly of myosin II filaments is regulated in non-muscle cells: 1) transient increases in Ca2+ binds Ca2+ calmodulin which activates myosin light chain kinase (MLCK) 2) MLCK phosphorylates two of the light chains associated with the myosin head - this has two effects 1) release of myosin II from a binding site on the head, allowing myosin II to form bipolar filaments 2) a change in the conformation of the myosin head exposing the actin binding site allows interaction between AF and myosin II 3) There is additional regulation of MLCK which involves Rho...active Rho (Rho-GTP) activates Rho kinase which promotes the activation of MLCK 4) Additionally, Rho kinase also phosphorylates and inactivates MLCK phosphatase therefore preventing the dephosphorylation and inactivation of MLCK contractibility is baed solely on whether or not myosin is active In non-muscle cells organized contractile bundles of AFs and myosin II filaments are formed transiently to preform specific functions and then disassemble (a dynamic sys- tem) - when there is no need for the filaments anymore - myosin II is relatively abundant in the cortex of non-muscle cells - stress fibers are prominent in cultured fibroblasts, represent a temporary contractible bundle of AFs and myosin II - bundles of AF are able to contract due to myosin II filaments - membrane ruffling is driven by ATP production Therefore, Rho has a double effect on MLCK - enhancing its activity and inhibit- ing its inactivation - so in non-muscle cells interaction between AF and myosin II involves myosin-based regulatory system that response to increasing Ca2+ concentrations and active Rho In skeletal muscle, interactions between stable AFs and myosin II thick filaments is regulated a different way - sacromere - in skeletal muscle tropomyos
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