Isomorphisms in tropomyosin modulate binding, flexibility and thin filament function

原肌球蛋白的同构调节结合、柔韧性和细丝功能

• 批准号: RGPIN-2017-06010
• 负责人: Heeley, David
• 金额: $ 1.89万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=681543
• 关键词: Isomorphisms; tropomyosin; modulate; binding; flexibility

Living organisms move. The most spectacular examples are muscles that have a striped appearance under the microscope. We rely on them daily for blood circulation, posture, speed activates the motor myosin. The outcome is substantial ATP hydrolysis and contraction. When Ca(II) is taken back up, the reverse happens and relaxation ensues. Tropomyosin is able to do this because: (a) it polymerises with itself, forming a flexible, continuous strand and (b) its interactions with other proteins (eg actin, troponin) are Ca(II)-sensitive.******Part (I). 'Tuning' tropomyosin. The diversity of animal locomotion is an outcome of different types of muscle - fast, slow and cardiac - that deploy isoforms of the myofilament proteins to contract and relax. Protein isoforms are like cousins; they bear a family resemblance but have distinguishing features (eg slightly different amino acid sequences). How tropomyosin contributes to muscle diversity has long-been an enigma. ******The major isoforms of tropomyosin are Tpm1.1 (formerly ) ). They share 39 amino acid substitutions. The 'big' Q. What do they do differently? was answered only recently (Lohmeier-Vogel 50) not yet studied at the protein level.*********Part (II). Tropomyosin in extreme conditions The problem of cold for a protein is rigidity. During the winter, the N. Atlantic approaches freezing, a drop of > 30 oC compared to the warm-blooded (mammalian) scenario. Yet this is a natural marine habitat. A 'big' Q. is: How does tropomyosin avoid being straitjacketed'? Recent work (Fudge & Heeley 2015) has shown the existence of 3 'flexing' strategies (fewer ion pairs, more glycine & polar residues in core sites) within salmon Tpm1.1. The effect of these 'cold isomorphisms' on salmon Tpm1.1 function - polymerisation, troponin binding & regulation - will be probed by interchange of amino acids with the thermally-stable mammalian homologue. Part (II), as with Part (I), will provide information on tropomyosin's functional landscape (ie binding sites). *****

生物体移动。最壮观的例子是肌肉在显微镜下有条纹外观。我们每天都依靠它们来进行血液循环，姿势，速度激活运动肌球蛋白。结果是大量的ATP水解和收缩。当Ca（II）被重新摄取时，发生相反的情况，弛豫增强。原肌球蛋白能够做到这一点是因为：（a）它与自身聚合，形成一个灵活的，连续的链和（B）它与其他蛋白质（如肌动蛋白，肌钙蛋白）的相互作用是Ca（II）敏感的。第一部分。“调整”原肌球蛋白。动物运动的多样性是不同类型肌肉的结果-快，慢和心脏-部署肌丝蛋白的亚型收缩和放松。蛋白质异构体就像表兄弟;它们具有家族相似性，但具有区别性特征（例如略有不同的氨基酸序列）。原肌球蛋白如何促进肌肉多样性一直是个谜。** 原肌球蛋白的主要同种型是Tpm 1.1（以前））。 它们共有39个氨基酸替换。“大”Q他们有什么不同的做法？ 直到最近才得到回答（Lohmeier-Vogel 50），尚未在蛋白质水平上进行研究。第（二）部分。极端条件下的原肌球蛋白蛋白蛋白质的冷问题是刚性。在冬季，N.大西洋接近冰点，与温血动物（哺乳动物）的情况相比下降了30摄氏度以上。然而，这是一个天然的海洋栖息地。一个大Q。原肌球蛋白如何避免被束缚？最近的工作（Fudge & Heeley 2015）已经表明在鲑鱼Tpm 1.1中存在3种“弯曲”策略（更少的离子对，更多的甘氨酸和核心位点中的极性残基）。这些“冷同构”对鲑鱼Tpm1.1功能的影响-聚合，肌钙蛋白结合和调节-将通过与热稳定的哺乳动物同源物交换氨基酸来探测。第二部分，与第一部分一样，将提供原肌球蛋白的功能景观（即结合位点）的信息。*****