The UNC-45 Chaperone as a Modulator of Myosin Biogenesis and Function

UNC-45 伴侣作为肌球蛋白生物合成和功能的调节剂

• 批准号: 9789043
• 负责人: GUY Martin BENIAN
• 金额: $ 30.69万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789043
• 关键词: Address; Amino Acids; Animals; Binding; Biochemical; Biogenesis; Biological; Biological Assay; Biological Models; Biology; Biophysics; CRISPR/Cas technology; Caenorhabditis elegans; Cardiomyopathies; Cell division; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Data; Development; Drosophila genus; Equilibrium; Exposure to; Functional disorder; Genes; Head; Heat Stress Disorders; Heat-Shock Proteins 90; Heat-Shock Response; Hydrogen Peroxide; In Vitro; Investigation; Knowledge; Lead; Length; Mediating; Microfilaments; Molecular; Molecular Chaperones; Molecular Conformation; Motor; Muscle; Muscle Cells; Muscle Development; Muscle function; Mutagenesis; Mutation; Myofibrils; Myopathy; Myosin ATPase; Myosin Type II; Phenotype; Physiological; Process; Protein Isoforms; Proteins; Publishing; Recovery; Regulation; Research; Research Personnel; Role; Sarcomeres; Series; Site; Skeletal Muscle; Stress; Striated Muscles; Structure; System; Techniques; Testing; Thick Filament; Up-Regulation; Vertebrates; Work; cell motility; cell type; crystallinity; developmental disease; experimental study; human disease; in vivo; inhibitor/antagonist; insight; member; multidisciplinary; mutant; non-muscle myosin; novel; novel therapeutic intervention; novel therapeutics; premature; prevent; protein complex; protein folding; public health relevance; recruit; repaired; response; skeletal; stem; temperature sensitive mutant; tumor; tumor progression

 DESCRIPTION (provided by applicant): In this proposal we aim to elucidate the precise molecular mechanisms by which the chaperones UNC-45 and Hsp90 assist in the folding of the myosin head which is critical for sarcomere assembly during development and repair of stress-induced damage to sarcomeres in mature muscle. Developing an understanding of these mechanisms is a problem at the core of muscle development and function. It is also highly relevant to the folding and repair of the many classes of myosin molecules that are expressed in non-muscle tissues. Our recent discovery that myosin attains a novel conformation, which hydrolyzes ATP at the normal rate but with a greatly reduced ability to translocate actin filaments, in the presence of UNC-45 and is reversed by Hsp90, raises important questions as to the exact roles of these chaperones in myosin folding and repair and myofilament assembly. Guided by our recent published and preliminary studies, we hypothesize that during myosin assembly or repair, UNC-45 assists the myosin head to attain its native conformation and subsequently locks it in a state that prevents premature powerstrokes; this state is relieved by Hsp90 upon successful assembly into the sarcomere or repair of myosin heads. This hypothesis will be tested by using a combination of in vitro and in vivo analyses through a unique collaboration between two expert research labs. In Aim 1 we will use mutagenesis, biochemical and biophysical assays, including myosin-dependent actin filament gliding assays, to establish the UNC-45 domains and key amino acid regions that mediate the different unique functions of UNC-45. In Aims 2 and 3 we will use the power of C. elegans as a model system to examine the functional relationships between mutant UNC-45 proteins and sarcomere assembly (Aim 2), and the dynamics of association of UNC-45 and Hsp90 with themselves and with myosin during repair of damaged myosin heads (Aim 3). Our hypothesis, if confirmed, will represent a new paradigm in the biology of myosins, with potential novel therapeutic approaches not only for striated muscle disorders stemming from mutations in sarcomeric proteins (skeletal myopathies and cardiomyopathies), but also for the problem of tumor invasiveness.



项目成果

Mutational Analysis of the Structure and Function of the Chaperoning Domain of UNC-45B.

UNC-45B 陪伴结构域的结构和功能的突变分析。

• DOI: 10.1016/j.bpj.2020.07.012
• 发表时间: 2020
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Gaziova,Ivana;Moncrief,Taylor;Christian,CourtneyJ;Villarreal,Michael;Powell,Simon;Lee,Hubert;Qadota,Hiroshi;White,MarkA;Benian,GuyM;Oberhauser,AndresF
• 通讯作者: Oberhauser,AndresF

Meeting report – NSF-sponsored workshop ‘Progress and Prospects of Single-Molecule Force Spectroscopy in Biological and Chemical Sciences’

会议报告 — NSF 主办的研讨会 — 单分子力谱在生物和化学科学领域的进展与展望 —

• DOI: 10.1242/jcs.251421
• 发表时间: 2020
• 期刊: Journal of Cell Science
• 影响因子: 4
• 作者: Marszalek, Piotr E.;Oberhauser, Andres F.
• 通讯作者: Oberhauser, Andres F.

Animal models of sarcopenia.

• DOI: 10.1111/acel.13223
• 发表时间: 2020-10
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Christian CJ;Benian GM
• 通讯作者: Benian GM

The central domain of UNC-45 chaperone inhibits the myosin power stroke.

• DOI: 10.1002/2211-5463.12346
• 发表时间: 2018-01
• 期刊: FEBS open bio
• 影响因子: 2.6
• 作者: Bujalowski PJ;Nicholls P;Garza E;Oberhauser AF
• 通讯作者: Oberhauser AF

Mutations in conserved residues of the myosin chaperone UNC-45 result in both reduced stability and chaperoning activity.

肌球蛋白伴侣 UNC-45 保守残基的突变会导致稳定性和伴侣活性降低。

• DOI: 10.1002/pro.4180
• 发表时间: 2021
• 期刊: Protein science : a publication of the Protein Society
• 作者: Moncrief,Taylor;Matheny,CourtneyJ;Gaziova,Ivana;Miller,JohnM;Qadota,Hiroshi;Benian,GuyM;Oberhauser,AndresF
• 通讯作者: Oberhauser,AndresF