The complete gene sequence of titin, expression of an unusual ≈700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system

Marie Louise Bang, Thomas Centner, Friderike Fornoff, Adam J. Geach, Michael Gotthardt, Mark McNabb, Christian C. Witt, Dietmar Labeit, Carol Gregorio, Hendrikus "Henk" Granzier, Siegfried Labeit

Research output: Contribution to journalArticle

409 Citations (Scopus)

Abstract

Titin is a giant vertebrate striated muscle protein with critical importance for myofibril elasticity and structural integrity. We show here that the complete sequence of the human titin gene contains 363 exons, which together code for 38 138 residues (4200 kDa). In its central I-band region, 47 novel PEVK exons were found, which contribute to titin's extensible spring properties. Additionally, 3 unique I-band titin exons were identified (named novex-1 to -3). Novex-3 functions as an alternative titin C-terminus. The novex-3 titin isoform is ≈700 kDa in size and spans from Z1-Z2 (titin's N-terminus) to novex-3 (C-terminal exon). Novex-3 titin specifically interacts with obscurin, a 721-kDa myofibrillar protein composed of 57 Ig/FN3 domains, followed by one IQ, SH3, DH, and a PH domain at its C-terminus. The obscurin domains Ig48/Ig49 bind to novex-3 titin and target to the Z-line region when expressed as a GFP fusion protein in live cardiac myocytes. Immunoelectron microscopy detected the C-terminal Ig48/Ig49 obscurin epitope near the Z-line edge. The distance from the Z-line varied with sarcomere length, suggesting that the novex-3 titin/obscurin complex forms an elastic Z-disc to I-band linking system. This system could link together calcium-dependent, SH3-, and GTPase-regulated signaling pathways in close proximity to the Z-disc, a structure increasingly implicated in the restructuring of sarcomeres during cardiomyopathies.

Original languageEnglish (US)
Pages (from-to)1065-1072
Number of pages8
JournalCirculation Research
Volume89
Issue number11
StatePublished - Nov 23 2001
Externally publishedYes

Fingerprint

Connectin
Protein Isoforms
Genes
Exons
Sarcomeres
Striated Muscle
Immunoelectron Microscopy
Muscle Proteins
Myofibrils
GTP Phosphohydrolases
Elasticity
Cardiomyopathies
Cardiac Myocytes
Vertebrates
Epitopes
Proteins

Keywords

  • Cardiac myopathies
  • Obscurin
  • Striated muscle myofibrils
  • Titin/connectin
  • Z-disc signaling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

The complete gene sequence of titin, expression of an unusual ≈700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. / Bang, Marie Louise; Centner, Thomas; Fornoff, Friderike; Geach, Adam J.; Gotthardt, Michael; McNabb, Mark; Witt, Christian C.; Labeit, Dietmar; Gregorio, Carol; Granzier, Hendrikus "Henk"; Labeit, Siegfried.

In: Circulation Research, Vol. 89, No. 11, 23.11.2001, p. 1065-1072.

Research output: Contribution to journalArticle

Bang, ML, Centner, T, Fornoff, F, Geach, AJ, Gotthardt, M, McNabb, M, Witt, CC, Labeit, D, Gregorio, C, Granzier, HH & Labeit, S 2001, 'The complete gene sequence of titin, expression of an unusual ≈700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system', Circulation Research, vol. 89, no. 11, pp. 1065-1072.
Bang, Marie Louise ; Centner, Thomas ; Fornoff, Friderike ; Geach, Adam J. ; Gotthardt, Michael ; McNabb, Mark ; Witt, Christian C. ; Labeit, Dietmar ; Gregorio, Carol ; Granzier, Hendrikus "Henk" ; Labeit, Siegfried. / The complete gene sequence of titin, expression of an unusual ≈700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. In: Circulation Research. 2001 ; Vol. 89, No. 11. pp. 1065-1072.
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abstract = "Titin is a giant vertebrate striated muscle protein with critical importance for myofibril elasticity and structural integrity. We show here that the complete sequence of the human titin gene contains 363 exons, which together code for 38 138 residues (4200 kDa). In its central I-band region, 47 novel PEVK exons were found, which contribute to titin's extensible spring properties. Additionally, 3 unique I-band titin exons were identified (named novex-1 to -3). Novex-3 functions as an alternative titin C-terminus. The novex-3 titin isoform is ≈700 kDa in size and spans from Z1-Z2 (titin's N-terminus) to novex-3 (C-terminal exon). Novex-3 titin specifically interacts with obscurin, a 721-kDa myofibrillar protein composed of 57 Ig/FN3 domains, followed by one IQ, SH3, DH, and a PH domain at its C-terminus. The obscurin domains Ig48/Ig49 bind to novex-3 titin and target to the Z-line region when expressed as a GFP fusion protein in live cardiac myocytes. Immunoelectron microscopy detected the C-terminal Ig48/Ig49 obscurin epitope near the Z-line edge. The distance from the Z-line varied with sarcomere length, suggesting that the novex-3 titin/obscurin complex forms an elastic Z-disc to I-band linking system. This system could link together calcium-dependent, SH3-, and GTPase-regulated signaling pathways in close proximity to the Z-disc, a structure increasingly implicated in the restructuring of sarcomeres during cardiomyopathies.",
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T1 - The complete gene sequence of titin, expression of an unusual ≈700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system

AU - Bang, Marie Louise

AU - Centner, Thomas

AU - Fornoff, Friderike

AU - Geach, Adam J.

AU - Gotthardt, Michael

AU - McNabb, Mark

AU - Witt, Christian C.

AU - Labeit, Dietmar

AU - Gregorio, Carol

AU - Granzier, Hendrikus "Henk"

AU - Labeit, Siegfried

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N2 - Titin is a giant vertebrate striated muscle protein with critical importance for myofibril elasticity and structural integrity. We show here that the complete sequence of the human titin gene contains 363 exons, which together code for 38 138 residues (4200 kDa). In its central I-band region, 47 novel PEVK exons were found, which contribute to titin's extensible spring properties. Additionally, 3 unique I-band titin exons were identified (named novex-1 to -3). Novex-3 functions as an alternative titin C-terminus. The novex-3 titin isoform is ≈700 kDa in size and spans from Z1-Z2 (titin's N-terminus) to novex-3 (C-terminal exon). Novex-3 titin specifically interacts with obscurin, a 721-kDa myofibrillar protein composed of 57 Ig/FN3 domains, followed by one IQ, SH3, DH, and a PH domain at its C-terminus. The obscurin domains Ig48/Ig49 bind to novex-3 titin and target to the Z-line region when expressed as a GFP fusion protein in live cardiac myocytes. Immunoelectron microscopy detected the C-terminal Ig48/Ig49 obscurin epitope near the Z-line edge. The distance from the Z-line varied with sarcomere length, suggesting that the novex-3 titin/obscurin complex forms an elastic Z-disc to I-band linking system. This system could link together calcium-dependent, SH3-, and GTPase-regulated signaling pathways in close proximity to the Z-disc, a structure increasingly implicated in the restructuring of sarcomeres during cardiomyopathies.

AB - Titin is a giant vertebrate striated muscle protein with critical importance for myofibril elasticity and structural integrity. We show here that the complete sequence of the human titin gene contains 363 exons, which together code for 38 138 residues (4200 kDa). In its central I-band region, 47 novel PEVK exons were found, which contribute to titin's extensible spring properties. Additionally, 3 unique I-band titin exons were identified (named novex-1 to -3). Novex-3 functions as an alternative titin C-terminus. The novex-3 titin isoform is ≈700 kDa in size and spans from Z1-Z2 (titin's N-terminus) to novex-3 (C-terminal exon). Novex-3 titin specifically interacts with obscurin, a 721-kDa myofibrillar protein composed of 57 Ig/FN3 domains, followed by one IQ, SH3, DH, and a PH domain at its C-terminus. The obscurin domains Ig48/Ig49 bind to novex-3 titin and target to the Z-line region when expressed as a GFP fusion protein in live cardiac myocytes. Immunoelectron microscopy detected the C-terminal Ig48/Ig49 obscurin epitope near the Z-line edge. The distance from the Z-line varied with sarcomere length, suggesting that the novex-3 titin/obscurin complex forms an elastic Z-disc to I-band linking system. This system could link together calcium-dependent, SH3-, and GTPase-regulated signaling pathways in close proximity to the Z-disc, a structure increasingly implicated in the restructuring of sarcomeres during cardiomyopathies.

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