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BIOL 4510
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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 Tension (% Max) (Starling) 20 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 are least 15 different classes of myosin; the myosins involved in force generation and movement in muscle (cardiac, skeletal and smooth muscle are comprised of Type II. Type II dimerizes…two myosin moleculae are connected by coil-coil structures in the tail Type I is the most primitive2+yosin: moves molecular cargos….are Ca -dependent via Calcium/calmodulin binding in neck region Myosins are generally large proteins with a total molecular mass of ~500,000 Da. Each 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 force generation and ATPase activity Neck An -helix with sequences that bind light chains The light chains contribute to the stability of the helix in the neck region and modulate ATPase activity. The head and neck domains are referred to as the S1 domain, also called meromyosin Tail Myosin heavy chain tails form an -helical coiled-coil tail domain (tail). 2 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) 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 These two isoforms can co-assemble in 3 possible ways: V1= fast) V = intermediate) 2 3 V 3 (slow) In the human heart, the myosin heavy chains, MHC and MHC, are expressed in a tissue-specific manner. The MHC is preferentially expressed in atria. ~90% of ventricle is MHC (rest is MHC ). In the fetal and neonatal heart, MHC is expressed in the ventricles and atria. There are species differences in MHC expression. The rat ventricle predominantly expresses MHC rabbit hearts expresses 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. - slower myosin is more energy efficient (general principle in biology, the faster you want reactions to occur the more inefficient the system) - human heart disease levels of MHC,go up and MHC gprs down,. - speed of contraction slows in heart disease - mutations in myosin genes were the first to be associated with inherited hypertrophic cardiomyopathy - 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) 4 • 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 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. 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. 2+ ATPase of MHC is modulated by actin and Ca Ca 2+ (1-3 µM) stimulates ATPase in presence of actin Ca 2+ influences the rate of movement 2+ Increase of Ca to >~10 µM decreases velocity immediately followed by a gradual decay Myosin Light Chain 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 Ca2+ regulation resides on thin filament (more later) Crystal structure of the myosin head and neck domain (S1) 5 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.
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