X-ray Crystallographic and Molecular Dynamic Analyses of Drosophila melanogaster Embryonic Muscle Myosin Define Domains Responsible for Isoform-Specific Properties

Caldwell, James T.; Mermelstein, Daniel J.; Walker, Ross C.; Bernstein, Sanford I.; Huxford, Tom

doi:10.1016/j.jmb.2019.11.013

Cited by 4 publications

(4 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To study the effects of mutations in these residues, we modeled the Drosophila IFM myosin heavy chain sequence onto the human β-cardiac myosin motor domain (PDB: 4P7H), as shown in Figure 1 A. Note that the R249 and D262 residues and the general structure of the transducer are conserved between human and Drosophila myosins [ 26 ]. The wild-type myosin model shows that positively charged R249 residue interacts with negatively charged residue D262 with a 2.6 Å contact distance ( Figure 1 B).…”

Section: Resultsmentioning

confidence: 99%

Myosin Transducer Inter-Strand Communication Is Critical for Normal ATPase Activity and Myofibril Structure

Kronert

Hsu

Madan

et al. 2022

Biology

Self Cite

View full text Add to dashboard Cite

The R249Q mutation in human β-cardiac myosin results in hypertrophic cardiomyopathy. We previously showed that inserting this mutation into Drosophila melanogaster indirect flight muscle myosin yields mechanical and locomotory defects. Here, we use transgenic Drosophila mutants to demonstrate that residue R249 serves as a critical communication link within myosin that controls both ATPase activity and myofibril integrity. R249 is located on a β-strand of the central transducer of myosin, and our molecular modeling shows that it interacts via a salt bridge with D262 on the adjacent β-strand. We find that disrupting this interaction via R249Q, R249D or D262R mutations reduces basal and actin-activated ATPase activity, actin in vitro motility and flight muscle function. Further, the R249D mutation dramatically affects myofibril assembly, yielding abnormalities in sarcomere lengths, increased Z-line thickness and split myofibrils. These defects are exacerbated during aging. Re-establishing the β-strand interaction via a R249D/D262R double mutation restores both basal ATPase activity and myofibril assembly, indicating that these properties are dependent upon transducer inter-strand communication. Thus, the transducer plays an important role in myosin function and myofibril architecture.

show abstract

Section: Resultsmentioning

confidence: 99%

Myosin Transducer Inter-Strand Communication Is Critical for Normal ATPase Activity and Myofibril Structure

Kronert

Hsu

Madan

et al. 2022

Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Analysis of the recently solved crystal structure of Drosophila MHC motor domain suggest that the alternative relay and the alternative converter affect the mobility of these regions, thus contributing to the observed functional difference in Drosophila embryonic isoform and the indirect flight muscle isoform (Caldwell et al. , 2020). Located at the distal end of the relay, three residues (Ile 508 , Asn 509 , and Asp 511 ) participate in the interactions with Arg 759 of the converter (Bloemink et al.…”

Section: Discussionmentioning

confidence: 99%

Alternative relay regulates the adenosine triphosphatase activity of Locusta migratoria striated muscle myosin

Hao,

Liu,

Zhang

et al. 2023

Insect Science

View full text Add to dashboard Cite

Locust (Locusta migratoria) has a single striated muscle myosin heavy chain (Mhc) gene, which contains 5 clusters of alternative exclusive exons and 1 differently included penultimate exon. The alternative exons of Mhc gene encode 4 distinct regions in the myosin motor domain, that is, the N‐terminal SH3‐like domain, one lip of the nucleotide‐binding pocket, the relay, and the converter. Here, we investigated the role of the alternative regions on the motor function of locust muscle myosin. Using Sf9‐baculovirus protein expression system, we expressed and purified 5 isoforms of the locust muscle myosin heavy meromyosin (HMM), including the major isoform in the thorax dorsal longitudinal flight muscle (FL1) and 4 isoforms expressed in the abdominal intersegmental muscle (AB1 to AB4). Among these 5 HMMs, FL1‐HMM displayed the highest level of actin‐activated adenosine triphosphatase (ATPase) activity (hereafter referred as ATPase activity). To identify the alternative region(s) responsible for the elevated ATPase activity of FL1‐HMM, we produced a number of chimeras of FL1‐HMM and AB4‐HMM. Substitution with the relay of AB4‐HMM (encoded by exon‐14c) substantially decreased the ATPase activity of FL1‐HMM, and conversely, the relay of FL1‐HMM (encoded by exon‐14a) enhanced the ATPase activity of AB4‐HMM. Mutagenesis showed that the exon‐14a‐encoded residues Gly474 and Asn509 are responsible for the elevated ATPase activity of FL1‐HMM. Those results indicate that the alternative relay encoded by exon‐14a/c play a key role in regulating the ATPase activity of FL1‐HMM and AB4‐HMM.

show abstract

“…Recently, NDP52 was shown to attract the ULK1 complex to damaged mitochondria 7 or cytosolic pathogens 8 by binding to a C-terminal region of FIP200. Once recruited, ULK1 initiates the formation of the phagophore directly at the cargo 9 . The recruitment of the ULK1 complex is facilitated by TANK-binding kinase 1 (TBK1) 7 , 8 .…”

Section: Introductionmentioning

confidence: 99%

FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates

Schlütermann

Berleth

Deitersen

et al. 2021

Sci Rep

View full text Add to dashboard Cite

The protein kinase TBK1 is a central regulator of innate immune responses and autophagy, and ablation of either function has been linked to neuroinflammatory or degenerative diseases. Autophagy is an intracellular process that recycles old or damaged proteins and organelles. In recent years, the TBK1-dependent regulation of autophagy pathways has been characterized. However, the autophagy-dependent regulation of TBK1 activity awaits further clarification. Here, we observed that TBK1 is recruited to SQSTM1/p62-containing aggregates via the selective autophagy receptor TAX1BP1. In these aggregates, TBK1 phosphorylates SQSTM1/p62 at serine 403 and thus presumably regulates the efficient engulfment and clearance of these structures. We found that TBK1 activation is strongly increased if FIP200, a component of the autophagy-inducing ULK1 complex, is not present or cannot bind to TAX1BP1. Given our collective findings, we hypothesize that FIP200 ensures the inducible activation of TBK1 at SQSTM1/p62 condensates.

show abstract

X-ray Crystallographic and Molecular Dynamic Analyses of Drosophila melanogaster Embryonic Muscle Myosin Define Domains Responsible for Isoform-Specific Properties

Cited by 4 publications

References 108 publications

Myosin Transducer Inter-Strand Communication Is Critical for Normal ATPase Activity and Myofibril Structure

Myosin Transducer Inter-Strand Communication Is Critical for Normal ATPase Activity and Myofibril Structure

Alternative relay regulates the adenosine triphosphatase activity of Locusta migratoria striated muscle myosin

FIP200 controls the TBK1 activation threshold at SQSTM1/p62-positive condensates

Contact Info

Product

Resources

About