The Palladin/Myotilin/Myopalladin Family of Actin‐Associated Scaffolds

Otey, Carol; Rachlin, Andrew; Moza, Monica; Arneman, Daniel; Carpén, Olli

doi:10.1016/s0074-7696(05)46002-7

Cited by 99 publications

(102 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[27][28][29][30][31] The largest palladin isoform, with a molecular weight of B200 kDa, has a similar domain arrangement as demonstrated for myopalladin with two amino-terminal and three carboxy-terminal immunoglobulin-like domains. 31 Remarkably, the sequence motif 961 PVTFTC 966 in the third immunoglobulin-like domain of myopalladin is identical to the amino-acid sequence 1017-1021 in the corresponding palladin domain, for which structural data have recently been reported (PDB 2DM2).…”

Section: Discussionmentioning

confidence: 76%

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

et al. 2012

View full text Add to dashboard Cite

on behalf of the German Competence Network Heart Failure Recently, missense mutations in titin-associated proteins have been linked to the pathogenesis of dilated cardiomyopathy (DCM). The objective of this study was to search for novel disease-associated mutations in the two human titin-binding proteins myopalladin and its amino-terminal-interacting partner cardiac ankyrin-repeat protein (CARP). In a cohort of 255 cases with familial and sporadic DCM, we analyzed the coding regions and all corresponding intron flanks located in the MYPN and CARPencoding ANKRD1 gene. Two heterozygous missense mutations were detected in the MYPN gene (p.R955W and p.P961L), but neither of these mutations was found in 300 healthy controls. Both mutations were located in the a-actinin-binding region of myopalladin. Endomyocardial biopsies from the p.R955W carrier showed normal subcellular localization of myopalladin and a-actinin in cardiac myocytes, while their regular sarcomeric staining pattern was significantly disrupted in the p.P961L carrier, indicating that disturbed myofibrillogenesis and altered sarcomere assembly are the cause of the disease. In the ANKRD1 gene, we identified synonymous base exchanges (c.108T4C and c.-79C4T, respectively), but no non-synonymous mutations. In summary, we have identified novel missense mutations in the third immunoglobulin-like domain of myopalladin, which have either no or profound effects on the molecular composition of the sarcomere. According to our epidemiological data, the prevalence of ANKRD1 mutations seems to be lower than that of its binding partner myopalladin, indicating the clinical significance of myopalladin for the functional integrity of the sarcomeric apparatus and the protection against DCM.

show abstract

Section: Discussionmentioning

confidence: 76%

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

et al. 2012

View full text Add to dashboard Cite

show abstract

“…However, kettin might be functionally homologous to palladin (Parast and Otey, 2000), myopalladin (Bang et al, 2001), and myotilin (Salmikangas et al, 1999), which have two to five Ig-repeats and localize to the Z-lines of vertebrate striated muscle. These proteins are critical for actin filament reorganization in nonmuscle cells (Boukhelifa et al, 2001(Boukhelifa et al, , 2003Salmikangas et al, 2003;Otey et al, 2005) and myofibril assembly in muscle cells (Bang et al, 2001;Salmikangas et al, 2003;Otey et al, 2005). In particular, myotilin directly binds to actin filaments, and its mutations in the human gene are associated with limb girdle muscular dystrophy 1A (Salmikangas et al, 1999) and myofibrillar myopathy (Selcen and Engel, 2004), which are termed myotilinopathies (Goebel, 2005;Olive et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegansKettin, a Large Immunoglobulin-like Repeat Protein, Binds to Filamentous Actin and Provides Mechanical Stability to the Contractile Apparatuses in Body Wall Muscle

Ono

Mohri

et al. 2006

MBoC

View full text Add to dashboard Cite

Kettin is a large actin-binding protein with immunoglobulin-like (Ig) repeats, which is associated with the thin filaments in arthropod muscles. Here, we report identification and functional characterization of kettin in the nematode Caenorhabditis elegans. We found that one of the monoclonal antibodies that were raised against C. elegans muscle proteins specifically reacts with kettin (Ce-kettin). We determined the entire cDNA sequence of Ce-kettin that encodes a protein of 472 kDa with 31 Ig repeats. Arthropod kettins are splice variants of much larger connectin/titin-related proteins. However, the gene for Ce-kettin is independent of other connectin/titin-related genes. Ce-kettin localizes to the thin filaments near the dense bodies in both striated and nonstriated muscles. The C-terminal four Ig repeats and the adjacent non-Ig region synergistically bind to actin filaments in vitro. RNA interference of Ce-kettin caused weak disorganization of the actin filaments in body wall muscle. This phenotype was suppressed by inhibiting muscle contraction by a myosin mutation, but it was enhanced by tetramisole-induced hypercontraction. Furthermore, Ce-kettin was involved in organizing the cytoplasmic portion of the dense bodies in cooperation with ␣-actinin. These results suggest that kettin is an important regulator of myofibrillar organization and provides mechanical stability to the myofibrils during contraction. INTRODUCTIONIn muscle cells, the actin cytoskeleton is highly differentiated to form the myofibrils that are specialized for producing contractile forces. In addition to actin and myosin as the essential contractile components, regulatory components for the contractile activity are integrated into the structure (Squire, 1997). Despite the fact that many myofibrillar components have been identified, little is known about how these components functionally interact to assemble and maintain the myofibrils in living cells (Littlefield and Fowler, 1998;Gregorio and Antin, 2000;Clark et al., 2002). In particular, the assembly process of actin filaments is complex. During development, actin-monomer binding proteins, including profilin, and actin depolymerizing factor/cofilin regulate actin filament dynamics (Obinata, 1993;Obinata et al., 1997; Ono, 2003a,b). However, in mature myofibrils, these proteins are no longer major components of the thin filaments, and filament binding proteins, such as tropomyosin and ␣-actinin, and end-capping proteins, such as CapZ and tropomodulin, become the major actin-associated proteins. However, the list of actin binding proteins in muscle is still growing and cellular functions of many of these proteins are not clearly understood.Kettin is a large protein of 500-700 kDa found in the Z-discs and the I-bands of arthropod muscles (Bullard et al., 2000;Bullard et al., 2002Bullard et al., , 2006. Kettin directly binds to actin filaments with high-affinity (Lakey et al., 1993;Maki et al., 1995;van Straaten et al., 1999). Proteolytic removal of kettin by calpain from the Z-discs causes ...

show abstract

“…While CDKN1A (which encodes for p21 CIP1 ) and MTOR had been shown previously to regulate senescence or senescence-related phenotypes, this is the first evidence suggesting that MYOT and UBE2E1 regulate senescence. MYOT encodes for myotilin, whose main known function is to be part of the Z-disc of sarcomeres (Otey et al 2005). Despite identifying multiple shRNAs targeting MYOT in the screen and confirming their effects with two independent shRNAs, expression of MYOT was hard to detect in IMR90 cells.…”

Section: Discussionmentioning

confidence: 99%

Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence

et al. 2017

View full text Add to dashboard Cite

Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A. We developed an innovative approach that integrates singlecell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates. Our data unveiled regulation of senescence as a novel way by which mechanistic target of rapamycin (mTOR) influences reprogramming. On one hand, mTOR inhibition blunts the induction of cyclin-dependent kinase (CDK) inhibitors (CDKIs), including p16 INK4a , p21 CIP1 , and p15 INK4b , preventing OSKM-induced senescence. On the other hand, inhibition of mTOR blunts the senescence-associated secretory phenotype (SASP), which itself favors reprogramming. These contrasting actions contribute to explain the complex effect that mTOR has on reprogramming. Overall, our study highlights the advantage of combining functional screens with scRNA-seq to accelerate the discovery of pathways controlling complex phenotypes.

show abstract

The Palladin/Myotilin/Myopalladin Family of Actin‐Associated Scaffolds

Cited by 99 publications

References 88 publications

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

Caenorhabditis elegansKettin, a Large Immunoglobulin-like Repeat Protein, Binds to Filamentous Actin and Provides Mechanical Stability to the Contractile Apparatuses in Body Wall Muscle

Coupling shRNA screens with single-cell RNA-seq identifies a dual role for mTOR in reprogramming-induced senescence

Contact Info

Product

Resources

About