Harpers

MUSCLE & THE CYTOSKELETON / 561exhibits no ATPase activity and does not bind toF-actin.Heavy meromyosin (HMM; molecular mass about340 kDa) is a soluble protein that has both a fibrousportion and a globular portion (Figure 49–4). It exhibitsATPase activity and binds to F-actin. Digestionof HMM with papain generates two subfragments, S-1and S-2. The S-2 fragment is fibrous in character, hasno ATPase activity, and does not bind to F-actin.S-1 (molecular mass approximately 115 kDa) doesexhibit ATPase activity, binds L chains, and in the absenceof ATP will bind to and decorate actin with “arrowheads”(Figure 49–5). Both S-1 and HMM exhibitATPase activity, which is accelerated 100- to 200-fold bycomplexing with F-actin. As discussed below, F-actingreatly enhances the rate at which myosin ATPase releasesits products, ADP and P i . Thus, although F-actindoes not affect the hydrolysis step per se, its ability topromote release of the products produced by the ATPaseactivity greatly accelerates the overall rate of catalysis.CHANGES IN THE CONFORMATIONOF THE HEAD OF MYOSIN DRIVEMUSCLE CONTRACTIONHow can hydrolysis of ATP produce macroscopicmovement? Muscle contraction essentially consists ofthe cyclic attachment and detachment of the S-1 head ofmyosin to the F-actin filaments. This process can also bereferred to as the making and breaking of cross-bridges.The attachment of actin to myosin is followed by conformationalchanges which are of particular importancein the S-1 head and are dependent upon which nucleotideis present (ADP or ATP). These changes resultin the power stroke, which drives movement of actinfilaments past myosin filaments. The energy for thepower stroke is ultimately supplied by ATP, which ishydrolyzed to ADP and P i . However, the power strokeitself occurs as a result of conformational changes inthe myosin head when ADP leaves it.The major biochemical events occurring during onecycle of muscle contraction and relaxation can be representedin the five steps shown in Figure 49–6:(1) In the relaxation phase of muscle contraction,the S-1 head of myosin hydrolyzes ATP to ADP and P i ,but these products remain bound. The resultant ADP-P i -myosin complex has been energized and is in a socalledhigh-energy conformation.(2) When contraction of muscle is stimulated (viaevents involving Ca 2+ , troponin, tropomyosin, andactin, which are described below), actin becomes accessibleand the S-1 head of myosin finds it, binds it, andforms the actin-myosin-ADP-P i complex indicated.(3) Formation of this complex promotes the releaseof P i , which initiates the power stroke. This is followedby release of ADP and is accompanied by a largeconformational change in the head of myosin in relationto its tail (Figure 49–7), pulling actin about 10 nmtoward the center of the sarcomere. This is the powerstroke. The myosin is now in a so-called low-energystate, indicated as actin-myosin.(4) Another molecule of ATP binds to the S-1 head,forming an actin-myosin-ATP complex.(5) Myosin-ATP has a low affinity for actin, andactin is thus released. This last step is a key componentof relaxation and is dependent upon the bindingof ATP to the actin-myosin complex.ActinATP-MyosinH 2 OActin-MyosinATP51ATP4ADP-P i -MyosinActin-Myosin2ActinADP+P i3Actin-MyosinADP-P iFigure 49–5. The decoration of actin filaments withthe S-1 fragments of myosin to form “arrowheads.”(Courtesy of JA Spudich.)Figure 49–6. The hydrolysis of ATP drives the cyclicassociation and dissociation of actin and myosin in fivereactions described in the text. (Modified from Stryer L:Biochemistry, 2nd ed. Freeman, 1981.)