Cristina M Risi / Maicon Landim-Vieira / Betty Belknap / P Bryant Chase / Jose R Pinto / Vitold E Galkin /
PubMed Abstract
Cardiac muscle contraction/relaxation cycle depends on the rising and falling Ca levels in sarcomeres that control the extent of interactions between myosin-based thick and actin-based thin filaments. ...Cardiac muscle contraction/relaxation cycle depends on the rising and falling Ca levels in sarcomeres that control the extent of interactions between myosin-based thick and actin-based thin filaments. Cardiac thin filament (cTF) consists of actin, tropomyosin (Tm) that regulates myosin binding to actin, and troponin complex that governs Tm position upon Ca-binding. Troponin has three subunits - Ca-binding troponin C (TnC), Tm stabilizing troponin T (TnT), and inhibitory troponin I (TnI). TnT N-terminus (TnT1) interactions with actin stabilize the inhibited state of cTF. TnC, TnI, and Tm work in concert to control actomyosin interactions. Cryo-electron microscopy (cryo-EM) provided factual structures of healthy cTF, but structures of cTF carrying missense mutations linked to human cardiomyopathy are unknown. Variant Ile79Asn in human cardiac TnT (TnT-I79N) increases myofilament Ca sensitivity and slows cross-bridge kinetics, leading to severe hypertrophic/restrictive cardiomyopathy. Here, we used TnT-I79N mutation as a tool to examine the role of TnT1 in the complex mechanism of cTF regulation. Comparison of the cryo-EM structures of murine wild type and TnT-I79N native cTFs at systolic Ca levels (pCa = 5.8) demonstrates that TnT-I79N causes 1) dissociation of the TnT1 loop from its actin interface that results in Tm release to a more activated position, 2) reduced interaction of TnI C-terminus with actin-Tm, and 3) increased frequency of Ca-bound regulatory units. Our data indicate that the TnT1 loop is a crucial element of the allosteric regulatory network that couples Tn subunits and Tm to maintain adequate cTF response to physiological Ca levels during a heartbeat.
EMDB-47449, PDB-9e2e: The structure of the junction region of the wild-type murine native cardiac thin filament in Ca2+-free state Method: EM (single particle) / Resolution: 4.0 Å
EMDB-48447, PDB-9mo4: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-free state (lower strand) Method: EM (single particle) / Resolution: 5.3 Å
EMDB-48448, PDB-9mo5: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-bound partially activated state (lower strand) Method: EM (single particle) / Resolution: 5.3 Å
EMDB-48449, PDB-9mo6: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-free tilted state (lower strand) Method: EM (single particle) / Resolution: 5.3 Å
EMDB-48450, PDB-9mo7: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-bound fully activated state (lower strand) Method: EM (single particle) / Resolution: 5.2 Å
EMDB-48451, PDB-9mo8: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-free state (upper strand) Method: EM (single particle) / Resolution: 5.2 Å
EMDB-48452, PDB-9mo9: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-free rotated state (lower strand) Method: EM (single particle) / Resolution: 5.6 Å
EMDB-48453, PDB-9moa: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-free tilted state (lower strand) Method: EM (single particle) / Resolution: 5.4 Å
EMDB-48454, PDB-9mob: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-free state (upper strand) Method: EM (single particle) / Resolution: 5.5 Å
EMDB-48455, PDB-9moc: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-free rotated state (upper strand) Method: EM (single particle) / Resolution: 5.6 Å
EMDB-48456, PDB-9mod: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-free tilted state (upper strand) Method: EM (single particle) / Resolution: 5.7 Å
EMDB-48467, PDB-9moi: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-free rotated state (lower strand) Method: EM (single particle) / Resolution: 5.4 Å
EMDB-48468, PDB-9mok: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-free rotated state (upper strand) Method: EM (single particle) / Resolution: 5.6 Å
EMDB-48469, PDB-9mol: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-free tilted state (upper strand) Method: EM (single particle) / Resolution: 5.2 Å
EMDB-48470, PDB-9mom: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-bound partially activated state (upper strand) Method: EM (single particle) / Resolution: 5.1 Å
EMDB-48471, PDB-9mon: Structure of native murine cardiac thin filament at pCa=5.8 in Ca2+-bound fully activated state (upper strand) Method: EM (single particle) / Resolution: 5.2 Å
EMDB-48476, PDB-9moo: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-free state (lower strand) Method: EM (single particle) / Resolution: 5.2 Å
EMDB-48477, PDB-9mop: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-bound fully activated state (lower strand) Method: EM (single particle) / Resolution: 5.0 Å
EMDB-48482, PDB-9mou: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-bound partially activated state (upper strand) Method: EM (single particle) / Resolution: 5.6 Å
EMDB-48483, PDB-9mow: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-bound fully activated state (upper strand) Method: EM (single particle) / Resolution: 4.9 Å
EMDB-48484, PDB-9mox: Structure of native murine cardiac thin filament variant I79N in troponin T at pCa=5.8 in Ca2+-bound partially activated state (lower strand) Method: EM (single particle) / Resolution: 5.2 Å
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Keywords
mus musculus (house mouse)