User:Gregory Hoeprich/Sandbox 1

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<references/><references/>{{STRUCTURE_1c1g|PDB=1c1g|SCENE=}}
<references/><references/>{{STRUCTURE_1c1g|PDB=1c1g|SCENE=}}
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[[Image:Tropomyosin Dimer-2.png | thumb | left| 300x180px | alt text | '''Tropomyosin:''' Coiled-Coil Dimer, which is composed of two alpha helices [http://www.pdb.org/pdb/explore/explore.do?structureId=1C1G (1C1G)] ]][[Image:B Lehman1.jpg | thumb | 300 x 430px | left | alt text | '''Tropomyosin''' (seen in yello and red) wrapped around actin filaments, which are EM reconstructions with G-actin ribbion structures filling in the EM structure). (Picture generated from William Lehman's [http://www.bumc.bu.edu/phys-biophys/people/faculty/lehman/ Website]) ]]'''[[Tropomyosin]] (TM)''' is an [[actin]] binding protein, which consists of a coiled-coil dimer (see left) and forms a polymer along the length of actin by a head-to-tail overlap (along the major grove of actin, see down & left)<ref>Tropomyosins. I. Gunning, Peter, 1950- II. Series.[DNLM: 1. Tropomyosin. W1 AD559 v.644 2008 / WE 500 T856 2008]</ref>. The head-to-tail overlap allows flexibility between the tropomyosin dimers so it will lay unstrained along the filament<ref>Tropomyosins. I. Gunning, Peter, 1950- II. Series.[DNLM: 1. Tropomyosin. W1 AD559 v.644 2008 / WE 500 T856 2008]</ref>. Each tropomyosin molecule spans seven actin monomers within a filament and lays N- to C- terminally from actin's pointed to barbed end<ref name="Frye">PMID:20465283</ref>. The 284 amino acid helix has a length of 420 Angstroms and has a molecular weight around 65-70 kilodaltons (vertebrate tropomyosin)<ref name="Whitby">PMID:10651038</ref>. A few of tropomyosin's characteristics as an actin binding protein includes regulation, stabilization and recruitment.
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[[Image:Tropomyosin Dimer-2.png | thumb | left| 300x180px | alt text | '''Tropomyosin:''' Coiled-Coil Dimer, which is composed of two alpha helices [http://www.pdb.org/pdb/explore/explore.do?structureId=1C1G (1C1G)] ]][[Image:B Lehman1.jpg | thumb | 300 x 430px | left | alt text | '''Tropomyosin''' (seen in yello and red) wrapped around actin filaments, which are EM reconstructions with G-actin ribbion structures filling in the EM structure). (Picture generated from William Lehman's [http://www.bumc.bu.edu/phys-biophys/people/faculty/lehman/ Website]) ]]'''[[Tropomyosin]] (TM)''' is an [[actin]] binding protein, which consists of a coiled-coil dimer (see left) and forms a polymer along the length of actin by a head-to-tail overlap (along the major grove of actin, see down & left)<ref name="Gunning">Tropomyosins. I. Gunning, Peter, 1950- II. Series.[DNLM: 1. Tropomyosin. W1 AD559 v.644 2008 / WE 500 T856 2008]</ref>. The head-to-tail overlap allows flexibility between the tropomyosin dimers so it will lay unstrained along the filament<ref name="Gunning"/>. Each tropomyosin molecule spans seven actin monomers within a filament and lays N- to C- terminally from actin's pointed to barbed end<ref name="Frye">PMID:20465283</ref>. The 284 amino acid helix has a length of 420 Angstroms and has a molecular weight around 65-70 kilodaltons (vertebrate tropomyosin)<ref name="Whitby">PMID:10651038</ref>. A few of tropomyosin's characteristics as an actin binding protein includes regulation, stabilization and recruitment.
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Its role in muscle mechanics has been well established as it is a major regulatory component of the contractile apparatus, but its role in non-muscle systems is becoming evermore clear. In mammals, there are at least 40 known isoforms, which are generated by alternative splicing of multiple genes. These isoforms in non-muscle systems contribute to actin's stability by increasing filament rigidity and protecting the filament from actin severing proteins, like [[gelsolin]] or [http://en.wikipedia.org/wiki/Cofilin cofilin]. The different isoforms also aid in recruitment of various proteins, including myosin (a family of molecular motors). The reason for tropomyosin's diversity is not well known, but it is thought to exist to function at different developmental stages in some species as well as function in specific cells of higher multicellular organisms.
Its role in muscle mechanics has been well established as it is a major regulatory component of the contractile apparatus, but its role in non-muscle systems is becoming evermore clear. In mammals, there are at least 40 known isoforms, which are generated by alternative splicing of multiple genes. These isoforms in non-muscle systems contribute to actin's stability by increasing filament rigidity and protecting the filament from actin severing proteins, like [[gelsolin]] or [http://en.wikipedia.org/wiki/Cofilin cofilin]. The different isoforms also aid in recruitment of various proteins, including myosin (a family of molecular motors). The reason for tropomyosin's diversity is not well known, but it is thought to exist to function at different developmental stages in some species as well as function in specific cells of higher multicellular organisms.

Revision as of 23:39, 9 May 2011

PDB ID 1c1g

Drag the structure with the mouse to rotate
1c1g, resolution 7.00Å ()
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Tropomyosin: Coiled-Coil Dimer, which is composed of two alpha helices (1C1G)
Tropomyosin: Coiled-Coil Dimer, which is composed of two alpha helices (1C1G)
Tropomyosin (seen in yello and red) wrapped around actin filaments, which are EM reconstructions with G-actin ribbion structures filling in the EM structure). (Picture generated from William Lehman's Website)
Tropomyosin (seen in yello and red) wrapped around actin filaments, which are EM reconstructions with G-actin ribbion structures filling in the EM structure). (Picture generated from William Lehman's Website)
Tropomyosin (TM) is an actin binding protein, which consists of a coiled-coil dimer (see left) and forms a polymer along the length of actin by a head-to-tail overlap (along the major grove of actin, see down & left)[1]. The head-to-tail overlap allows flexibility between the tropomyosin dimers so it will lay unstrained along the filament[1]. Each tropomyosin molecule spans seven actin monomers within a filament and lays N- to C- terminally from actin's pointed to barbed end[2]. The 284 amino acid helix has a length of 420 Angstroms and has a molecular weight around 65-70 kilodaltons (vertebrate tropomyosin)[3]. A few of tropomyosin's characteristics as an actin binding protein includes regulation, stabilization and recruitment.


Its role in muscle mechanics has been well established as it is a major regulatory component of the contractile apparatus, but its role in non-muscle systems is becoming evermore clear. In mammals, there are at least 40 known isoforms, which are generated by alternative splicing of multiple genes. These isoforms in non-muscle systems contribute to actin's stability by increasing filament rigidity and protecting the filament from actin severing proteins, like gelsolin or cofilin. The different isoforms also aid in recruitment of various proteins, including myosin (a family of molecular motors). The reason for tropomyosin's diversity is not well known, but it is thought to exist to function at different developmental stages in some species as well as function in specific cells of higher multicellular organisms.

The details of its structure/function relationship defines its role in different cell systems and disease states, this page further discuss tropomyosin's structure and function.

Contents

Structure/Function Relationships

Tropomyosin's Alpha Helices are represented in ribbon (Chain A) and ball and stick form (Chain B, without side chains). The yellow lines represent the polar contacts within the protein backbone, which stabilize the helical structure.
Tropomyosin's Alpha Helices are represented in ribbon (Chain A) and ball and stick form (Chain B, without side chains). The yellow lines represent the polar contacts within the protein backbone, which stabilize the helical structure.
As determined by the Structural Classification of Protein's (SCOP) Database, Tropomyosin is categorized as follows (general to specific):
  1. Class: coiled-coil
  2. Fold: parallel coiled-coil
  3. Superfamily: tropomyosin
  4. Family: pig [1c1g]

Tropomyosin Dimer: Click on Green Links (right) to see hydrophobic and ionic interactions between the two alpha helices

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Helical Wheel Diagram Representation of Tropopomyosin: The coiled-coil dimer is stabilized by hydrophobic and ionic interactions (red=hydrophobic, blue=polar & green=charged).
Helical Wheel Diagram Representation of Tropopomyosin: The coiled-coil dimer is stabilized by hydrophobic and ionic interactions (red=hydrophobic, blue=polar & green=charged).
Categorization of tropomyosin's describes a unique pattern of amino acids within the primary structure of the alpha helices that comprise the dimer interface. The unique amino acid pattern, found within all coiled-coil proteins, is a heptad repeat, which follows a similar pattern to: H-P-P-H-C-P-C, where H is hydrophobic, P is polar and C is charged. This heptad repeat forms a right handed alpha helical secondary structure (see right for alpha helix secondary structure). This alpha helix is special in that it forms a hydrophobic strip along one side, which will interface with an adjacent alpha helix that also contains the heptad repeat and hydrophobic strip. These strips aid in the dimerization of tropomyosin and is important in the characteristic coiled-coil domain.


This coiled-coil domain is represented as a helical wheel diagram (see right), whereby the four amino acids (two from each alpha chain) that are adjacent to each other contribute to a , represented in red, while the four amino acids (two from each alpha chain) flanking the hydrophobic core provide an , or salt-bridge represented as green. Both the hydrophobic and ionic interactions contribute to the stability of the dimer.

The amino acids from each alpha chain interact with each other uniquely in that side chains of the helices interfacing will pack together in a knobs in holes arrangement. This is accomplished by the ridges of one helix fitting between the grooves (between amino acids) of the adjacent helix. This packing allows for the two alpha helices to wrap tightly around each other in a left handed supercoil conformation further stabilizing the tropomyosin dimer.

Tropomyosin, as mentioned above, will form a long polymer along the length of actin in a head-to-tail overlap.

Tropomyosin end-to-end overlap region (3MTU)

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This occurs as the amino acids from the of one dimer overlaps with the amino acids of the of another dimer. There are several in the overlap region, which consist of ionic, hydrophobic and non-polar interactions. Interestingly, the most variation seen among tropomyosin isoforms is in the overlap region, which will affect polymer formation along the actin filament.


Post-Translational Modifications

There are two types of post-translational modifications to tropomyosin: acetylation and phosphorylation.

Tropomyosin in Muscle and Non-Muscle Systems

Muscle tissue is comprised of many muscle fibers or cells. Those muscle fibers consist of myofibrils that contain a series of contractile units called sarcomeres. Within this unit contains thick filaments, comprised mainly of myosin, and thin filaments, which contains actin, tropomyosin and troponin. Tropomyosin in striated muscle systems (skeletal and cardiac) acts to inhibit the myosin cross-bridges from binding to the myosin binding site on thin filaments, this tropomyosin state is in the "Blocked" position. When the muscle is stimulated, there is a rise in intracellular calcium stemming from a cascade of cellular processes. As the calcium is bathing the sarcomere, it will bind to the troponin complex, which is bound to both actin and tropomyosin. The troponin will displace the tropomyosin from a "Blocked" to a "Closed" position. This transition allows the myosin head to interact weakly with the myosin binding site. The tropomyosin is displaced to its final position, "Open" state, along actin filament as myosin binds to its site. These three tropomyosin states along the filament is referred to as the three state model. As the intracellular calcium concentration falls, the troponin no longer is able to displace tropomyosin and it will transition back to the "Blocked" state.

In non-muscle systems, as mentioned above, tropomyosin performs a wide variety of functions inside of cells. One of the specific functions tropomyosin performs within cells is recruitment of different myosin motors. Clayton et al 2010 showed actin decorated with tropomyosin increased myosin-V (cargo transporter) motility as opposed to bare actin[4]. It was also shown that myosin-I (cargo transporter and tension senor) lost its motility function on actin decorated with tropomyosin[4]. Further evidence from a related paper, Stark et al 2010, shows tropomyosin increases the affinity of myosin-II to actin filaments[5]. So actin with tropomyosin appears to spatially regulate motor activity and thus cellular function.


Evolutionary Conservation

Solved Tropomyosin Structures

3mtu, 3mud – cTPM alpha-1 – chicken
1ic2 - cTPM alpha-1 (mutant)
2w49, 2w4u – cTnnC+cTnnT+cTnnI+cTPM alpha-1+cActin
2z5h – yTPM alpha-1 N-terminal+C-terminal+GNC4 leucine zipper+TnnT – yeast
2z5i - yTPM alpha-1 N-terminal+C-terminal+GNC4 leucine zipper
2efr, 2efs, 2d3e - rTPM alpha-1 C-terminal+GNC4 leucine zipper – rabbit
1kql - TPM alpha-1 C-terminal+GNC4 leucine zipper - rat
1mv4 - TPM alpha-1 C-terminal – rat
2g9j - TPM alpha-1 TM9A+GNC4 – rat
2b9c – TPM mid region – rat
1c1g – TPM – pig
2tma – TPM - model


References

  1. ↑ 1.0 1.1 Tropomyosins. I. Gunning, Peter, 1950- II. Series.[DNLM: 1. Tropomyosin. W1 AD559 v.644 2008 / WE 500 T856 2008]
  2. ↑ Frye J, Klenchin VA, Rayment I. Structure of the tropomyosin overlap complex from chicken smooth muscle: insight into the diversity of N-terminal recognition . Biochemistry. 2010 Jun 15;49(23):4908-20. PMID:20465283 doi:10.1021/bi100349a
  3. ↑ Whitby FG, Phillips GN Jr. Crystal structure of tropomyosin at 7 Angstroms resolution. Proteins. 2000 Jan 1;38(1):49-59. PMID:10651038
  4. ↑ 4.0 4.1 Clayton JE, Sammons MR, Stark BC, Hodges AR, Lord M. Differential regulation of unconventional fission yeast myosins via the actin track. Curr Biol. 2010 Aug 24;20(16):1423-31. Epub 2010 Aug 12. PMID:20705471 doi:10.1016/j.cub.2010.07.026
  5. ↑ Stark BC, Sladewski TE, Pollard LW, Lord M. Tropomyosin and myosin-II cellular levels promote actomyosin ring assembly in fission yeast. Mol Biol Cell. 2010 Mar 15;21(6):989-1000. Epub 2010 Jan 28. PMID:20110347 doi:10.1091/mbc.E09-10-0852

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Gregory Hoeprich

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