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Lecture 11

BIOL 4510 Lecture 11-contract-proteins-1-revised.pdf

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Department
Biology
Course
BIOL 4510
Professor
Peter Backxx
Semester
Fall

Description
BIOL4510 / KINE 4510 Contractile Proteins 1 Peter Backx 2012 There are two properties of muscle you need to fully understand: 1) The force-length relationship 100 80 Myofilament overlap 60 Cardiac 40 Muscle (Starling) T20sion (% Max) 0 1.0 1.4 1.8 2.2 2.6 3.0 3.4 3.8 Sarcomere Length (m) 2) The dependence of force generation on the intracellular Ca 2+ levels. Ca 2+ acts as a catalyst for activating the ATPase in muscle for the purposes of conversion of chemical energy into force. 1 Heavy Filament Myosin Myosin is the molecular motor of the contractile protein machinery. It is the protein that converts chemical energy from ATP to mechanical energy, thus generating force and movement. There 17 different classes of myosin; myosins are involved in force generation and movement in muscle (cardiac, skeletal and smooth muscle are comprised of Type II myosins. Type II dimerizes…two myosin molecule are connected by coil-coil structures in the tail Type I is the most primitive myosin: moves molecular cargos like vesicles within cells; they are Ca -dependent (i.e. activated by a rise in 2+ intracellular Ca ) via Calcium/calmodulin binding in neck region Myosins are generally large proteins with a total molecular mass/weight of ~500,000 Da. Each myosin pair (the molecular unit of the thick filament) is comprised of: a tail, a neck and a head region Head The head region is the site of ATPase activity…ATP binding and hydrolysis is associated with changes in molecular structure that can be harnessed via the organizational structure of the sarcomere and myofibrils to generate force and move. Neck Myosin molecules have a neck with an -helix structure with amino acid sequences that bind light chains. The light chains contribute to the stability of the helix in the neck region and modulate (increase) ATPase activity. Tail Myosin heavy chain tails form an -helical coiled-coil tail domain (tail) that holds the two 2 myosins (in a dimer) together. This is also the region that allows for self-assembly into thick fiaments. Individual long tails of myosin interact with each other allowing myosin molecules to assemble into thick filaments. About 150 myosin dimers molecules polymerize in a thick filament (about 300 myosin heads/thick filament). The myosin is arranged in the thick filament in a nearly crystalline-like structure: every 14.5nanometers there are three cross bridges (each with 2 myosins) projecting from the thick filament (at 120 relative to one another). Each triplicate is rotated relative to the adjacent triplicate by 40 degrees. Therefore the repeat structure along the filament is 43.5 nanometers. 3 Myosin Heavy Chain (MHC) Cardiac There are two types of cardiac myosin heavy chains (MHC and MHC isoforms) MHC = fast MHC = slow  myosin ATPase = 5 *  myosin ATPase  myosin ATPase is thought to be more “energetically efficient”  and -myosin heavy chains are separate gene products. A common theme in biology (and biochemistry) is that reactions that take place quickly are often less efficient than slow reactions: the price you pay for speed is a reduced efficiency. These two isoforms can co-assemble in 3 possible ways: V1= fast) V2= intermediate) V = (slow) 3 In the human heart, the myosin heavy chains, MHC and MHC, are expressed in a tissue-specific manner. The MHC is preferentially expressed in human atria. ~90% of the myosin in the human ventricles is MHC (rest is MHC ). In human fetal and neonatal hearts, MHC is the predominant myosin expressed in the ventricles and atria. There are species differences in MHC expression. The rat ventricle predominantly expresses MHC rabbit ventricles express MHC and MHC MHC is found primarily in large mammals, which correlates with speed of contraction and heart rate; large mammals have slower heart rates and slower contraction. Human MHC contains 1939 amino acids residues while MHC contains 1935 amino acids. They only differ by 131 amino acids, mainly confined to regions of biological significance in the head domain such as the N-terminus, the ATP binding pocket, the actin binding cleft, the light chain binding domain and in the two hinge regions further down in the rod (tail) domain. ATPase of MHC is modulated by actin and Ca 2+ 2+ Ca 2+ (1-3 µM) stimulates ATPase in presence of actin Ca influences the rate of movement Increase of Ca 2+to >~10 µM decreases velocity immediately followed by a gradual decay - human heart disease levels of MHC goes up and MHC goes down,. - speed of contraction slows in heart disease - mutations in myosin genes were the first gene mutations to be associated with inherited hypertrophic cardiomyopathy 4 - heart on the left (above) is hypertrophic cardiomyopathy, heart on right is normal. - Mutations of contractile proteins can cause massive hypertrophy. Why would the heart do this? Answer compensation Skeletal In developing skeletal muscle, MHC-emb (embryonic) and MHC-neo (neonatal) are expressed In post-natal skeletal muscle there are 4 MHC isoforms • MHC (also referred to as MHC slow, same as cardiac MHC), IIA, IIB, and IIX (rodents) • MHC/slow, IIA, and IIX (humans although IIB gene is present, it does not seem to be expressed) These isoforms >80% identical (i.e., their amino acid sequences are < 20% different) MHC IIa MHC IIB MHC Most muscle have a combination of fibers (fast, intermediate and slow). The exact combination depends on the muscle and previous training. Each motor unit will innervate only one type of fiber. Muscle contractions in most muscles show a temporal sequence: slow followed by fast followed by intermediate. 5 Myosin Light Chain The type of myosin matches up with type of myosin light chains: different myosin light chains for MHC versus MHC myosin in the human heart. There are two types of myosin light chains (MLC), essential and regulatory, which are associated with the neck region of MHC myosin. The essential MLC is also referred to as MLC-1 or alkali MLC. It is called essential because myosin head will not work well without this chain. The regulatory MLC is also known as MLC-2 or phosphorylatable MLC. It is phosphorylated by myosin light chain kinase. Phosphorylation modulates myosin ATPase rate and increases Ca 2+ sensitivity (although most of Ca 2+ regulation resides on thin filament (more later)) Crystal structure of the myosin head and neck domain (S1) showing the different binding domains and the MLC1and MLC2 binding to the neck region Cardiac Isoforms In the human heart, there are two essential MLC isoforms, the MLC1sb (ventricle) and MLC1sa atrium). Both are regarded as slow. - the developing human embryo expresses MLCemb/atria in the whole heart and skeletal muscle. MLC-1emb/atrial protein levels decrease in ventricles to undetectable levels during early postnatal development (due to thyroid hormone) but persistent expression occurs in the atrium throughout adult life. Skeletal Muscle Isoforms Fast skeletal muscle (MHC IIA, IIB, IIX): MLC1f or MLC3f as well as MLC2f Slow skeletal muscle (MHCslow): MLC1sa or MLC1sb (cardiac: atrial or ventricular) As well as MLC2s Embryonic skeletal muscle (MHCemb/a) MLC1emb or MLC1f as well as MLC2f Heart disease induces the expression of MLC1sb in the atrium and MLC1sa in the ventricle. The changes in gene expression th
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