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Cryo-EM structure of the human cardiac myosin filament

Cryo-EM structure of the human cardiac myosin filament

 
粗肌丝 bipolar polymers of myosin II
F1, Single-particle 3D reconstruction of the C-zone reveals the organization of titin, cMyBP-C and myosin heads and tails. F1, Single-particle 3D reconstruction of the C-zone reveals the organization of titin, cMyBP-C and myosin heads and tails.
F1, Single-particle 3D reconstruction of the C-zone reveals the organization of titin, cMyBP-C and myosin heads and tails.
Zones:
  • P zone: proximal
  • C zone: cMyBP-C-containing
  • D zone: distal zones
  • bare zone: lacking myosin heads
 
Myosin是myosin II dimer, myosin II contains:
  • tails: alpha-helical tails, proximal subfragment2(S2) and distal light meromyosin(LMM)
  • heads: motor, essential light chain(ELC) and regulatory light chain(RLC)
crowns form a repeat of 430A
 
two myosin binding proteins: cMyBP-C and Titin, consisting of immunoglobulin-like (Ig) and fibronectin-type-III-like (Fn) domains
  • cMyBP-C: forms the C zone, regulate myosin function
  • Titin: define thick filament architecture
 
diastole时，myosin filaments are switched off, forming interacting-heads motifs (IHMs)
IHMs: blocked head(BH) and free head(FH)
成为super-relaxed state(SRX)的基础。
 
myosin和cMyBP-C突变可能会引起HCM心肌肥大病；titin则与genetically associated DCM有关。
使用Mavacamten稳定IHM和SRX状态。
 

Questions

  • detailed myosin molecular structure
 

Main results

  • 3D structure of the human ventricular心室 filament C-zone at 6A, revealing in molecular detail the complex organization of myosin heads, tails, titin and cMyBP-C.
 
 

Results

 

Structure of the C-zone at 6A

 

Myosin heads

3 crowns:
  • CrD: crown 2, disordered
  • CrT: crown 3, tilted
  • CrH: crown 1, horizontal
与无脊椎动物的IHMs完全不同，3个crown都有各自独特的功能

Myosin tails

filament backbone
left-handed super-coiling of their paired α-helices
F3 f-gF3 f-g
F3 f-g
CrH(green): 一开始往backbone走，然后转回surface；
CrT(blue): 和CrH类似，但在一开始形成了backbone部分；
CrD(red): 完全和上面两个分离，一直都是靠近表面，和cMyBP-C and titin互作。
 
notion imagenotion image
相比于无脊椎动物，是一个更加进化的性状，能够flexible response
notion imagenotion image
 

Titin and cMyBP-C

notion imagenotion image
Titin:
两条链，super-repeat 11 domains, Ig–Fn–Fn–Ig–Fn–Fn–Fn–Ig–Fn–Fn–Fn
这两条链之间作用不多
 
cMyBP-C:
single strand，解析出了6 domains，C5-C10
同时C8-10是锚定在backbone上的。
 

Interactions between components

  • myosin heads with heads
  • myosin tails with tails
  • titin with myosin tails
  • cMyBP-C with myosin heads
  • cMyBP-C with myosin tails
但是，titin和cMyBP-C以及titin和myosin heads之间都是没有互作的。