Tropomodulin

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Tropomodulin

Tropomodulin (TMOD) is a protein which binds and caps the minus end of actin (the "pointed" end), regulating the length of actin filaments in muscle and non-muscle cells. [1]

Contents

The protein functions by physically blocking the spontaneous dissociation of ADP-bound actin monomers from the minus end of the actin fibre. This, along with plus end capping proteins, such as capZ stabilise the structure of the actin filament. End capping is particularly important when long-lived actin filaments are necessary, for example: in myofibrils. Inhibition of tropomodulin capping activity leads to dramatic increase in thin filament length from its pointed end. [2] [3]

Actin filaments have two differing ends where one is the fast-acting barbed end and the other is the slow growing pointed end. [4] Since TMOD binds to the pointed end of actin it is essential in cell morphology, cell movement, and muscle contraction. [4] TMOD has been identified as an erythrocyte with 359 amino acids and it is a globular protein. [5] When tropomyosin is not present Tropomodulin also assists in partially inhibiting elongation and depolymerization at the pointed filament ends. [6] The N-terminal of Tropomodulin is rod shaped. This portion then binds to the N-terminal part of the two tropomyosin that are on the opposite part of the actin filaments in the muscle and nonmuscle cells. [7] TMOD is able to have high-affinity binding through low-affinity interactions because of its ability to control subunit exchange of the pointed end of the actin filaments. [5] When looking at epithelial cells Tropomodulin sustains F-actin in the lateral cell membranes and the adherens junction. [8] Tropomodulin binds exclusively to the pointed filament ends and not to actin monomers or alongside actin filaments. [9] Tropomodulin is a 40-kD tropomyosin-binding protein that was originally isolated from the red blood cell membrane skeleton. [6] Tropomodulin is associated with Leiomodin as homologous proteins because both proteins play a role in muscle sarcomere thin filament formation and maintenance. [7] An ortholog that is identified with TMOD and structurally similar  is UNC-94. Where the UNC-94 protein is capping on the minus end of the actin filament. This protein like TMOD depends on the presence of tropomyosin in order to function properly. [7]

Genes

The TMOD genes are important for cell morphology, cell movement, and muscle contraction. [4] There are 4 identified Tropomodulin genes identified in humans: TMOD1, TMOD2, TMOD3, and TMOD4. The 4 identified genes are also recognized as Isoforms. There are also known orthologs of these isoforms in mice. [10] Known tropomodulin homologs have been identified in flies (Drosophila), worms (C.elegans), rats, chicks, and mice. [9] [10] The TMOD genes are expressed at different levels in human tissue. The different levels can be identified as: the first level is heart and skeletal muscle, then the next level is found  in brain, lung, and pancreas, then the last level in placenta, liver, and kidney. [5] Using the lab technique PCR TMOD gene was isolated and identified to have a total of 9 exons, allowing for the assumption that alternative promoters for tissue-specific expression and regulation. [5] TMOD1, TMOD3, and TMOD4 are the only isoforms that are found in muscles. TMOD2 is the only identified isoform that is only found in the brain and not in any muscles like the other isoforms. The two isoforms that are associated with neurons are TMOD1 and TMOD2. [7] The functions of each isoform can vary depending on the location of the Tropomyosin and actin filaments. Since the TMOD isoforms can influence stability of skeleton cells and regulate actin it can then be seen as essential for embryonic development. [7]

Related Research Articles

<span class="mw-page-title-main">Smooth muscle</span> Involuntary non-striated muscle

Smooth (soft) muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations. It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit muscle, the whole bundle or sheet of smooth muscle cells contracts as a syncytium.

<span class="mw-page-title-main">Microfilament</span> Filament in the cytoplasm of eukaryotic cells

Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other proteins in the cell. Microfilaments are usually about 7 nm in diameter and made up of two strands of actin. Microfilament functions include cytokinesis, amoeboid movement, cell motility, changes in cell shape, endocytosis and exocytosis, cell contractility, and mechanical stability. Microfilaments are flexible and relatively strong, resisting buckling by multi-piconewton compressive forces and filament fracture by nanonewton tensile forces. In inducing cell motility, one end of the actin filament elongates while the other end contracts, presumably by myosin II molecular motors. Additionally, they function as part of actomyosin-driven contractile molecular motors, wherein the thin filaments serve as tensile platforms for myosin's ATP-dependent pulling action in muscle contraction and pseudopod advancement. Microfilaments have a tough, flexible framework which helps the cell in movement.

<span class="mw-page-title-main">Sarcomere</span> Repeating unit of a myofibril in a muscle cell

A sarcomere is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells which are formed during embryonic myogenesis. Muscle fibers contain numerous tubular myofibrils. Myofibrils are composed of repeating sections of sarcomeres, which appear under the microscope as alternating dark and light bands. Sarcomeres are composed of long, fibrous proteins as filaments that slide past each other when a muscle contracts or relaxes. The costamere is a different component that connects the sarcomere to the sarcolemma.

<span class="mw-page-title-main">Actin</span> Family of proteins

Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over 100 μM; its mass is roughly 42 kDa, with a diameter of 4 to 7 nm.

<span class="mw-page-title-main">Myosin</span> Superfamily of motor proteins

Myosins are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility.

<span class="mw-page-title-main">Tropomyosin</span> Protein

Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in many animal and fungal cells. In animals, it is an important component of the muscular system which works in conjunction with troponin to regulate muscle contraction. It is present in smooth and striated muscle tissues, which can be found in various organs and body systems, including the heart, blood vessels, respiratory system, and digestive system. In fungi, tropomyosin is found in cell walls and helps maintain the structural integrity of cells.

<span class="mw-page-title-main">Myofilament</span> The two protein filaments of myofibrils in muscle cells

Myofilaments are the three protein filaments of myofibrils in muscle cells. The main proteins involved are myosin, actin, and titin. Myosin and actin are the contractile proteins and titin is an elastic protein. The myofilaments act together in muscle contraction, and in order of size are a thick one of mostly myosin, a thin one of mostly actin, and a very thin one of mostly titin.

<span class="mw-page-title-main">ADF/Cofilin family</span> Family of actin-binding proteins

ADF/cofilin is a family of actin-binding proteins associated with the rapid depolymerization of actin microfilaments that give actin its characteristic dynamic instability. This dynamic instability is central to actin's role in muscle contraction, cell motility and transcription regulation.

<span class="mw-page-title-main">Nebulette</span> Protein-coding gene in the species Homo sapiens

Nebulette is a cardiac-specific isoform belonging to the nebulin family of proteins. It is encoded by the NEBL gene. This family is composed of 5 members: nebulette, nebulin, N-RAP, LASP-1 and LASP-2. Nebulette localizes to Z-discs of cardiac muscle and appears to regulate the length of actin thin filaments.

<span class="mw-page-title-main">Actin, alpha skeletal muscle</span> Protein-coding gene in the species Homo sapiens

Actin, alpha skeletal muscle is a protein that in humans is encoded by the ACTA1 gene.

<span class="mw-page-title-main">TPM1</span> Protein-coding gene in the species Homo sapiens

Tropomyosin alpha-1 chain is a protein that in humans is encoded by the TPM1 gene. This gene is a member of the tropomyosin (Tm) family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells.

<span class="mw-page-title-main">Actin, cytoplasmic 2</span> Protein-coding gene in the species Homo sapiens

Actin, cytoplasmic 2, or gamma-actin is a protein that in humans is encoded by the ACTG1 gene. Gamma-actin is widely expressed in cellular cytoskeletons of many tissues; in adult striated muscle cells, gamma-actin is localized to Z-discs and costamere structures, which are responsible for force transduction and transmission in muscle cells. Mutations in ACTG1 have been associated with nonsyndromic hearing loss and Baraitser-Winter syndrome, as well as susceptibility of adolescent patients to vincristine toxicity.

<span class="mw-page-title-main">TPM2</span> Protein-coding gene in the species Homo sapiens

β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene. β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.

<span class="mw-page-title-main">MYH10</span> Protein-coding gene in the species Homo sapiens

Myosin-10 also known as myosin heavy chain 10 or non-muscle myosin IIB (NM-IIB) is a protein that in humans is encoded by the MYH10 gene. Non-muscle myosins are expressed in a wide variety of tissues, but NM-IIB is the only non-muscle myosin II isoform expressed in cardiac muscle, where it localizes to adherens junctions within intercalated discs. NM-IIB is essential for normal development of cardiac muscle and for integrity of intercalated discs. Mutations in MYH10 have been identified in patients with left atrial enlargement.

<span class="mw-page-title-main">Tropomodulin 1</span> Protein-coding gene in the species Homo sapiens

Tropomodulin-1 is a protein that in humans is encoded by the TMOD1 gene.

<span class="mw-page-title-main">CAPZA2</span> Protein-coding gene in the species Homo sapiens

F-actin-capping protein subunit alpha-2 also known as CapZ-alpha2 is a protein that in humans is encoded by the CAPZA2 gene.

<span class="mw-page-title-main">Tropomodulin 3</span> Protein-coding gene in the species Homo sapiens

Tropomodulin-3 is a protein that in humans is encoded by the TMOD3 gene.

<span class="mw-page-title-main">Tropomodulin 4</span> Protein-coding gene in the species Homo sapiens

Tropomodulin 4 (muscle) also known as TMOD4 is a protein which in humans is encoded by the TMOD4 gene.

<span class="mw-page-title-main">Tropomodulin 2</span> Protein-coding gene in the species Homo sapiens

Tropomodulin 2 (neuronal) also known as TMOD2 is a protein which in humans is encoded by the TMOD2 gene.

<span class="mw-page-title-main">Cofilin-2</span> Protein found in humans

Cofilin 2 (muscle) also known as CFL2 is a protein which in humans is encoded by the CFL2 gene.

References

  1. Rao JN, Madasu Y, Dominguez R (July 2014). "Mechanism of actin filament pointed-end capping by tropomodulin". Science. 345 (6195): 463–467. Bibcode:2014Sci...345..463R. doi:10.1126/science.1256159. PMC   4367809 . PMID   25061212.
  2. Gregorio CC, Weber A, Bondad M, Pennise CR, Fowler VM (September 1995). "Requirement of pointed-end capping by tropomodulin to maintain actin filament length in embryonic chick cardiac myocytes". Nature. 377 (6544): 83–86. Bibcode:1995Natur.377...83G. doi:10.1038/377083a0. PMID   7544875. S2CID   4279512.
  3. Gunning PW, Ghoshdastider U, Whitaker S, Popp D, Robinson RC (June 2015). "The evolution of compositionally and functionally distinct actin filaments". Journal of Cell Science. 128 (11): 2009–2019. doi: 10.1242/jcs.165563 . PMID   25788699.
  4. 1 2 3 4 Kostyukova AS, Choy A, Rapp BA (October 2006). "Tropomodulin binds two tropomyosins: a novel model for actin filament capping". Biochemistry. 45 (39): 12068–12075. doi:10.1021/bi060899i. PMC   2596622 . PMID   17002306.
  5. 1 2 3 4 "Entry - *190930 - TROPOMODULIN 1; TMOD1 - OMIM". www.omim.org. Retrieved 2023-11-28.
  6. 1 2 Weber A, Pennise CR, Babcock GG, Fowler VM (December 1994). "Tropomodulin caps the pointed ends of actin filaments". The Journal of Cell Biology. 127 (6 Pt 1): 1627–35. doi:10.1083/jcb.127.6.1627. PMC   2120308 . PMID   7798317.
  7. 1 2 3 4 5 "Tropomodulin - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2023-11-28.
  8. 1 2 3 4 5 6 7 8 9 10 "Tropomodulins".
  9. 1 2 Weber A, Pennise CR, Fowler VM (December 1999). "Tropomodulin increases the critical concentration of barbed end-capped actin filaments by converting ADP.P(i)-actin to ADP-actin at all pointed filament ends". The Journal of Biological Chemistry. 274 (49): 34637–45. doi: 10.1074/jbc.274.49.34637 . PMID   10574928.
  10. 1 2 3 Cox PR, Siddique T, Zoghbi HY (2001-10-17). "Genomic organization of Tropomodulins 2 and 4 and unusual intergenic and intraexonic splicing of YL-1 and Tropomodulin 4". BMC Genomics. 2 (1): 7. doi: 10.1186/1471-2164-2-7 . PMC   59888 . PMID   11716785.
  11. Kuruba B, Starks N, Josten MR, Naveh O, Wayman G, Mikhaylova M, Kostyukova AS (August 2023). "Effects of Tropomodulin 2 on Dendritic Spine Reorganization and Dynamics". Biomolecules. 13 (8): 1237. doi: 10.3390/biom13081237 . PMC   10515316 . PMID   37627302.
  12. 1 2 Jin C, Chen Z, Shi W, Lian Q (May 2019). "Tropomodulin 3 promotes liver cancer progression by activating the MAPK/ERK signaling pathway". Oncology Reports. 41 (5): 3060–3068. doi: 10.3892/or.2019.7052 . PMID   30864730. S2CID   76665802.
  13. 1 2 Sui Z, Nowak RB, Sanada C, Halene S, Krause DS, Fowler VM (July 2015). "Regulation of actin polymerization by tropomodulin-3 controls megakaryocyte actin organization and platelet biogenesis". Blood. 126 (4): 520–530. doi:10.1182/blood-2014-09-601484. PMC   4513252 . PMID   25964668.