# TCAP

## Overview
The TCAP gene encodes the protein titin-cap, also known as telethonin, which is a crucial component of the sarcomeric Z-disk in both skeletal and cardiac muscle tissues. Titin-cap is a small, 19-kDa protein that plays a significant role in muscle structure and function by interacting with the N-terminal Z1-Z2 domains of titin, a large protein essential for the elasticity and integrity of muscle fibers (Gregorio1998The; Cheng2009Molecular). As a sarcomeric protein, titin-cap is involved in the assembly and maintenance of myofibrils, contributing to the structural organization of the sarcomere (Gregorio1998The). Beyond its structural role, titin-cap is implicated in muscle cell differentiation and growth, interacting with regulatory proteins such as myostatin and myogenic factors (Zhang2011Transcriptional; Markert2008TCAP). Mutations in the TCAP gene are associated with various muscular and cardiac disorders, including hypertrophic and dilated cardiomyopathies, as well as limb-girdle muscular dystrophy type 2G (Francis2014Novel; Hayashi2004Tcap).

## Structure
The TCAP gene encodes a protein known as titin-cap or telethonin, which is a 19-kDa protein localized to the Z-disk of skeletal and cardiac muscle. The primary structure of TCAP consists of 167 amino acids, with a molecular weight of approximately 19 kDa (Valle1997Telethonin; Cheng2009Molecular). The protein contains an immunoglobulin-like domain, which is crucial for its interaction with the N-terminal immunoglobulin domains Z1 and Z2 of titin, a large sarcomeric protein (Gregorio1998The; Cheng2009Molecular).

The secondary structure of TCAP includes potential phosphorylation motifs, particularly in a 27-residue-long COOH-terminal serine/proline and basic residue-rich domain, although this domain is not required for interaction with titin (Gregorio1998The). The tertiary structure involves the folding of these elements into a compact domain, facilitating its role in muscle function. TCAP functions as a monomer and lacks a quaternary structure.

Post-translational modifications, such as phosphorylation, are significant for TCAP's function, influencing its interaction with titin and other proteins (Cheng2009Molecular). These modifications are essential for muscle development and sarcomeric integrity (Cheng2009Molecular).

## Function
The TCAP gene encodes the titin-cap protein, also known as telethonin, which plays a crucial role in maintaining the structural integrity of muscle cells. TCAP is a 19-kDa protein that interacts with the NH2-terminal Z1-Z2 domains of titin, a large protein that spans the Z-disc in muscle sarcomeres. This interaction is essential for the assembly and maintenance of the myofibril structure, particularly in cardiac and skeletal muscles (Gregorio1998The). TCAP is localized at the edges of the Z-line in muscle fibers, where it colocalizes with titin and α-actinin, suggesting its involvement in the structural organization of the sarcomere (Gregorio1998The).

In addition to its structural role, TCAP is involved in muscle cell differentiation and growth. It interacts with myostatin, a key regulator of muscle growth, and its expression is regulated by myogenic regulatory factors such as MyoD and myogenin (Zhang2011Transcriptional; Markert2008TCAP). TCAP's interaction with these factors suggests it may function as part of a regulatory loop between the contractile apparatus and muscle development genes, influencing myoblast proliferation and differentiation (Markert2008TCAP).

## Clinical Significance
Mutations in the TCAP gene, which encodes the titin-cap protein, are associated with several muscular and cardiac conditions. In the context of cardiomyopathies, specific mutations in TCAP have been linked to hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). For instance, the T137I and R153H mutations are associated with HCM, while the E132Q mutation is linked to DCM. These mutations affect the interaction of Tcap with other proteins, such as titin and calsarcin-1, which are crucial for sarcomeric organization and mechanical coupling in heart muscle (Hayashi2004Tcap).

In addition to cardiomyopathies, TCAP mutations are implicated in limb-girdle muscular dystrophy type 2G (LGMD2G). This condition is characterized by muscle weakness and atrophy, particularly in the proximal limbs. Mutations such as c.32C>A and c.26_33dupAGGTGTCG lead to truncated telethonin proteins, disrupting normal muscle function (Francis2014Novel). The absence of telethonin due to TCAP mutations results in muscle pathology similar to LGMD2G, as observed in both human patients and Tcap knockout mouse models (Markert2010Functional).

## Interactions
TCAP (titin-cap) is a sarcomeric protein that interacts with several other proteins, playing a crucial role in muscle structure and function. It specifically binds to the NH2-terminal Z1-Z2 domains of titin, a giant protein essential for muscle elasticity and structural integrity. This interaction is necessary for the assembly and maintenance of myofibril structure, as both Z1 and Z2 domains are required for binding TCAP (Gregorio1998The).

TCAP also interacts with the potassium channel β-subunit minK. The cytoplasmic region of minK binds to the C-terminal region of TCAP, distinct from its titin-binding site. This interaction is regulated by phosphorylation at Ser157 of TCAP, which negatively affects the binding with minK (Furukawa2001Specific).

In addition to titin and minK, TCAP interacts with muscle LIM protein (MLP) and calsarcin-1 (CS-1). These interactions are significant for the mechanical coupling of sarcomeric contraction and stretching. Mutations in TCAP associated with dilated cardiomyopathy (DCM) impair its interaction with MLP, titin, and CS-1, while hypertrophic cardiomyopathy (HCM) mutations enhance interactions with titin and CS-1 (Hayashi2004Tcap).


## References


[1. (Furukawa2001Specific) Tetsushi Furukawa, Yasuko Ono, Hiroyuki Tsuchiya, Yoshifumi Katayama, Marie-Louise Bang, Dietmar Labeit, Siegfried Labeit, Nobuya Inagaki, and Carol C Gregorio. Specific interaction of the potassium channel β-subunit mink with the sarcomeric protein t-cap suggests a t-tubule-myofibril linking system. Journal of Molecular Biology, 313(4):775–784, November 2001. URL: http://dx.doi.org/10.1006/jmbi.2001.5053, doi:10.1006/jmbi.2001.5053. This article has 116 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1006/jmbi.2001.5053)

[2. (Markert2008TCAP) Chad D. Markert, Jie Ning, Jerry T. Staley, Laura Heinzke, Charles K. Childers, J. Andries Ferreira, Marybeth Brown, Aaron Stoker, Carol Okamura, and Martin K. Childers. Tcap knockdown by rna interference inhibits myoblast differentiation in cultured skeletal muscle cells. Neuromuscular Disorders, 18(5):413–422, May 2008. URL: http://dx.doi.org/10.1016/j.nmd.2008.03.010, doi:10.1016/j.nmd.2008.03.010. This article has 21 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.nmd.2008.03.010)

[3. (Hayashi2004Tcap) Takeharu Hayashi, Takuro Arimura, Manatsu Itoh-Satoh, Kazuo Ueda, Shigeru Hohda, Natsuko Inagaki, Megumi Takahashi, Hisae Hori, Michio Yasunami, Hirofumi Nishi, Yoshinori Koga, Hiroshi Nakamura, Masunori Matsuzaki, Bo Yoon Choi, Sung Won Bae, Cheol Woon You, Kyung Hoon Han, Jeong Euy Park, Ralph Knöll, Masahiko Hoshijima, Kenneth R. Chien, and Akinori Kimura. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. Journal of the American College of Cardiology, 44(11):2192–2201, December 2004. URL: http://dx.doi.org/10.1016/j.jacc.2004.08.058, doi:10.1016/j.jacc.2004.08.058. This article has 244 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.jacc.2004.08.058)

[4. (Markert2010Functional) C. D. Markert, M. P. Meaney, K. A. Voelker, R. W. Grange, H. W. Dalley, J. K. Cann, M. Ahmed, B. Bishwokarma, S. J. Walker, S. X. Yu, M. Brown, M. W. Lawlor, A. H. Beggs, and M. K. Childers. Functional muscle analysis of the tcap knockout mouse. Human Molecular Genetics, 19(11):2268–2283, March 2010. URL: http://dx.doi.org/10.1093/hmg/ddq105, doi:10.1093/hmg/ddq105. This article has 47 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1093/hmg/ddq105)

[5. (Gregorio1998The) Carol C. Gregorio, Karoly Trombitás, Thomas Centner, Bernhard Kolmerer, Gunter Stier, Kathleen Kunke, Koichi Suzuki, Franz Obermayr, Bernhard Herrmann, Henk Granzier, Hiroyuki Sorimachi, and Siegfried Labeit. The nh2 terminus of titin spans the z-disc: its interaction with a novel 19-kd ligand (t-cap) is required for sarcomeric integrity. The Journal of Cell Biology, 143(4):1013–1027, November 1998. URL: http://dx.doi.org/10.1083/jcb.143.4.1013, doi:10.1083/jcb.143.4.1013. This article has 247 citations.](https://doi.org/10.1083/jcb.143.4.1013)

[6. (Zhang2011Transcriptional) Shuang Zhang, Priya Londhe, Meiling Zhang, and Judith K. Davie. Transcriptional analysis of the titin cap gene. Molecular Genetics and Genomics, 285(3):261–272, February 2011. URL: http://dx.doi.org/10.1007/s00438-011-0603-6, doi:10.1007/s00438-011-0603-6. This article has 14 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00438-011-0603-6)

[7. (Francis2014Novel) Amirtharaj Francis, Balaraju Sunitha, Kandavalli Vinodh, Kiran Polavarapu, Shiva Krishna Katkam, Sailesh Modi, M. M. Srinivas Bharath, Narayanappa Gayathri, Atchayaram Nalini, and Kumarasamy Thangaraj. Novel tcap mutation c.32c>a causing limb girdle muscular dystrophy 2g. PLoS ONE, 9(7):e102763, July 2014. URL: http://dx.doi.org/10.1371/journal.pone.0102763, doi:10.1371/journal.pone.0102763. This article has 26 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0102763)

[8. (Valle1997Telethonin) G Valle, G Faulkner, A De Antoni, B Pacchioni, A Pallavicini, D Pandolfo, N Tiso, S Toppo, S Trevisan, and G Lanfranchi. Telethonin, a novel sarcomeric protein of heart and skeletal muscle. FEBS Letters, 415(2):163–168, September 1997. URL: http://dx.doi.org/10.1016/s0014-5793(97)01108-3, doi:10.1016/s0014-5793(97)01108-3. This article has 152 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/s0014-5793(97)01108-3)

[9. (Cheng2009Molecular) Hunjun Cheng, Xuewen Xu, Shuhong Zhao, Bang Liu, Mei Yu, and Bin Fan. Molecular cloning and expression profile analysis of porcine tcap gene. Molecular Biology Reports, 37(3):1641–1647, June 2009. URL: http://dx.doi.org/10.1007/s11033-009-9577-4, doi:10.1007/s11033-009-9577-4. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s11033-009-9577-4)