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2015 ; 519
(7541
): 114-7
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Structure of the F-actin-tropomyosin complex
#MMPMID25470062
von der Ecken J
; Müller M
; Lehman W
; Manstein DJ
; Penczek PA
; Raunser S
Nature
2015[Mar]; 519
(7541
): 114-7
PMID25470062
show ga
Filamentous actin (F-actin) is the major protein of muscle thin filaments, and
actin microfilaments are the main component of the eukaryotic cytoskeleton.
Mutations in different actin isoforms lead to early-onset autosomal dominant
non-syndromic hearing loss, familial thoracic aortic aneurysms and dissections,
and multiple variations of myopathies. In striated muscle fibres, the binding of
myosin motors to actin filaments is mainly regulated by tropomyosin and troponin.
Tropomyosin also binds to F-actin in smooth muscle and in non-muscle cells and
stabilizes and regulates the filaments there in the absence of troponin. Although
crystal structures for monomeric actin (G-actin) are available, a high-resolution
structure of F-actin is still missing, hampering our understanding of how
disease-causing mutations affect the function of thin muscle filaments and
microfilaments. Here we report the three-dimensional structure of F-actin at a
resolution of 3.7 Ċ in complex with tropomyosin at a resolution of 6.5 Ċ,
determined by electron cryomicroscopy. The structure reveals that the D-loop is
ordered and acts as a central region for hydrophobic and electrostatic
interactions that stabilize the F-actin filament. We clearly identify map density
corresponding to ADP and Mg(2+) and explain the possible effect of prominent
disease-causing mutants. A comparison of F-actin with G-actin reveals the
conformational changes during filament formation and identifies the D-loop as
their key mediator. We also confirm that negatively charged tropomyosin interacts
with a positively charged groove on F-actin. Comparison of the position of
tropomyosin in F-actin-tropomyosin with its position in our previously determined
F-actin-tropomyosin-myosin structure reveals a myosin-induced transition of
tropomyosin. Our results allow us to understand the role of individual mutations
in the genesis of actin- and tropomyosin-related diseases and will serve as a
strong foundation for the targeted development of drugs.
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