Titin's P-zone domains A164-167 are essential for thick filament structural arrangement

2026-03-12

PRE

Catherine Hoover Browne

Han, Seong-won

Farman, Gerrie P.

Smith, John E.

Kolb, Justin

Gohlke, Jochen

Langlais, Paul R.

Tonino, Paola

Mei Methawasin

van der Pijl, Robbert

Henk Granzier *

DOI：10.1085/jgp.202513891

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The sarcomeric protein titin plays a central role in thick filament structure and function through its modular A-band domains, including the understudied P-zone, which links the C-zone to the M-band. To investigate the first four domains of titin's P-zone (A164-A167), we deleted them in a mouse model (Ttn Delta A164-167). Echocardiography and cardiomyocyte mechanics revealed mild changes to diastolic function and enlargement of the heart, but preserved contractility. The EDL muscle showed contractile deficits at the whole muscle level and increased passive stiffness at the myofiber level. Immunoelectron and super-resolution microscopy revealed altered thick filament architecture, including a similar to 40-nm shift of titin and myosin binding protein-C epitopes toward the M-band, disruption of titin's alpha and beta conformations, and shorter thick filaments. The structural changes are consistent with the loss of a myosin helical repeat. These findings establish a key structural role of titin's P-zone domains A164-A167 in templating thick filament protein arrangement, including the importance of titin's alpha and beta conformations.

Keywords:

FRANK-STARLING MECHANISM

SKELETAL-MUSCLE FIBERS

SARCOMERIC M-BAND

MYBP-C

MOLECULAR MECHANICS

CALCIUM SENSITIVITY

CARDIAC-HYPERTROPHY

STRIATED-MUSCLE

GENE-EXPRESSION

HEART FUNCTION

Titin's P-zone domains A164-167 are essential for thick filament structural arrangement

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