National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
R01HL036153
米国
引用
ジャーナル: J Gen Physiol / 年: 2023 タイトル: Conformational changes linked to ADP release from human cardiac myosin bound to actin-tropomyosin. 著者: Matthew H Doran / Michael J Rynkiewicz / David Rasicci / Skylar M L Bodt / Meaghan E Barry / Esther Bullitt / Christopher M Yengo / Jeffrey R Moore / William Lehman / 要旨: Following binding to the thin filament, β-cardiac myosin couples ATP-hydrolysis to conformational rearrangements in the myosin motor that drive myofilament sliding and cardiac ventricular ...Following binding to the thin filament, β-cardiac myosin couples ATP-hydrolysis to conformational rearrangements in the myosin motor that drive myofilament sliding and cardiac ventricular contraction. However, key features of the cardiac-specific actin-myosin interaction remain uncertain, including the structural effect of ADP release from myosin, which is rate-limiting during force generation. In fact, ADP release slows under experimental load or in the intact heart due to the afterload, thereby adjusting cardiac muscle power output to meet physiological demands. To further elucidate the structural basis of this fundamental process, we used a combination of cryo-EM reconstruction methodologies to determine structures of the human cardiac actin-myosin-tropomyosin filament complex at better than 3.4 Å-resolution in the presence and in the absence of Mg2+·ADP. Focused refinements of the myosin motor head and its essential light chains in these reconstructions reveal that small changes in the nucleotide-binding site are coupled to significant rigid body movements of the myosin converter domain and a 16-degree lever arm swing. Our structures provide a mechanistic framework to understand the effect of ADP binding and release on human cardiac β-myosin, and offer insights into the force-sensing mechanism displayed by the cardiac myosin motor.
全体 : Human cardiac actin-tropomyosin-beta-myosin II complex bound to A...
全体
名称: Human cardiac actin-tropomyosin-beta-myosin II complex bound to ADPMg2+.
要素
複合体: Human cardiac actin-tropomyosin-beta-myosin II complex bound to ADPMg2+.
複合体: Cardiac F-actin complex
タンパク質・ペプチド: Actin, alpha cardiac muscle 1
複合体: Human beta-cardiac myosin II
タンパク質・ペプチド: beta-cardiac myosin II
複合体: Human cardiac tropomyosin
タンパク質・ペプチド: Tropomyosin alpha-1 chain
リガンド: MAGNESIUM ION
リガンド: ADENOSINE-5'-DIPHOSPHATE
-
超分子 #1: Human cardiac actin-tropomyosin-beta-myosin II complex bound to A...
超分子
名称: Human cardiac actin-tropomyosin-beta-myosin II complex bound to ADPMg2+. タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3 詳細: Cardiac actomyosin-tropomyosin complex with ADPMg2+ bound to the myosin motor head.
-
超分子 #2: Cardiac F-actin complex
超分子
名称: Cardiac F-actin complex / タイプ: complex / ID: 2 / 親要素: 1 / 含まれる分子: #2 / 詳細: F-actin forms the backbone of the complex
由来(天然)
生物種: Sus scrofa (ブタ)
-
超分子 #3: Human beta-cardiac myosin II
超分子
名称: Human beta-cardiac myosin II / タイプ: complex / ID: 3 / 親要素: 1 / 含まれる分子: #1 詳細: The motor domain of the myosin saturates the actin filament.
由来(天然)
生物種: Homo sapiens (ヒト)
-
超分子 #4: Human cardiac tropomyosin
超分子
名称: Human cardiac tropomyosin / タイプ: complex / ID: 4 / 親要素: 1 / 含まれる分子: #3 / 詳細: Tropomyosin wraps around the F-actin core.