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Novex-3, the tiny titin of muscle

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Abstract

The giant multi-functional striated muscle protein titin is the third most abundant muscle protein after myosin and actin. Titin plays a pivotal role in myocardial passive stiffness, structural integrity and stress-initiated signaling pathways. The complete sequence of the human titin gene contains three isoform-specific mutually exclusive exons [termed novel exons (novex)] coding for the I-band sequence, named novex-1 (exon 45), novex-2 (exon 46) and novex-3 (exon 48). Transcripts containing either the novex-1 or novex-2 exons code for the novex-1 and novex-2 titin isoforms. The novex-3 transcript contains a stop codon and polyA tail signal, resulting in an unusually small (∼700 kDa) isoform, referred to as novex-3 titin. This ‘tiny titin’ isoform extends from the Z-disc (N-terminus) to novex-3 (C-terminus) and is expressed in all striated muscles. Biochemical analysis of novex-3 titin in cardiomyocytes shows that obscurin, a vertebrate muscle protein, binds to novex-3 titin. The novex-3/obscurin complex localizes to the Z-disc region and may regulate calcium, and SH3- and GTPase-associated myofibrillar signaling pathways. Therefore, novex-3 titin could be involved in stress-initiated sarcomeric restructuring.

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, 85721, USA

    Dalma Kellermayer, John E. Smith III & Henk Granzier

  2. Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson, AZ, 85721, USA

    Dalma Kellermayer, John E. Smith III & Henk Granzier

Authors
  1. Dalma Kellermayer
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  2. John E. Smith III
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  3. Henk Granzier
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Correspondence to Henk Granzier.

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Funding

This study was funded by National Institutes of Health grant HL062881 (HG), HL118524 (HG) and Interdisciplinary Training in Cardiovascular Research T32 HL007249 (DK).

Conflict of interest

Dalma Kellermayer declares that she has no conflicts of interest. John E. Smith declares that he has no conflicts of interest. Henk Granzier declares that he has no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

This article is part of a Special Issue on ‘Titin and its Binding Proteins in Striated Muscles’ edited by Amy Li and Cristobal G. dos Remedios.

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Kellermayer, D., Smith, J.E. & Granzier, H. Novex-3, the tiny titin of muscle. Biophys Rev 9, 201–206 (2017). https://doi.org/10.1007/s12551-017-0261-y

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