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• W3041001808 abstract "Recent research has revealed that an adhesion complex based on cadherins and the motor protein myosin-7b (MYO7B) links the tips of intestinal microvilli. Choi et al. now report that a largely uncharacterized protein known as calmodulin-like protein 4 (CALML4) is a component of this adhesion complex and functions as a light chain for myosin-7b. Because the intermicrovillar adhesion complex is homologous to the myosin-7a (MYO7A)-based Usher syndrome complex and Choi et al. also report that CALML4 can bind to myosin-7a, this work also has important implications for research on myosin-7a and hereditary deaf-blindness. Recent research has revealed that an adhesion complex based on cadherins and the motor protein myosin-7b (MYO7B) links the tips of intestinal microvilli. Choi et al. now report that a largely uncharacterized protein known as calmodulin-like protein 4 (CALML4) is a component of this adhesion complex and functions as a light chain for myosin-7b. Because the intermicrovillar adhesion complex is homologous to the myosin-7a (MYO7A)-based Usher syndrome complex and Choi et al. also report that CALML4 can bind to myosin-7a, this work also has important implications for research on myosin-7a and hereditary deaf-blindness. Epithelial cells in many organs are covered by cylindrical protrusions of the apical plasma membrane known as microvilli. Microvilli contain a bundle of actin filaments at their core and provide a powerful model system for cytoskeletal research. Recent work has revealed that the actin-based motor protein myosin-7b localizes to the tips of intestinal microvilli, where its tail interacts with two scaffolding proteins, USH1C and ANKS4B, forming a complex that binds to the cytoplasmic domain of the cadherin-related protein CDHR2 (1Crawley S.W. Mooseker M.S. Tyska M.J. Shaping the intestinal brush border.J. Cell Biol. 2014; 207 (25422372): 441-45110.1083/jcb.201407015Crossref PubMed Scopus (118) Google Scholar, 2Li J. He Y. Lu Q. Zhang M. Mechanistic basis of organization of the harmonin/USH1C-mediated brush border microvilli tip-link complex.Dev. Cell. 2016; 36 (26812017): 179-18910.1016/j.devcel.2015.12.020Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 3Crawley S.W. Shifrin Jr., D.A. Grega-Larson N.E. McConnell R.E. Benesh A.E. Mao S. Zheng Y. Zheng Q.Y. Nam K.T. Millis B.A. Kachar B. Tyska M.J. Intestinal brush border assembly driven by protocadherin-based intermicrovillar adhesion.Cell. 2014; 157 (24725409): 433-44610.1016/j.cell.2014.01.067Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). The extracellular domain of CDHR2 in turn binds to the extracellular domain of another cadherin-related protein, CDHR5, forming a thin fibril that links the tips of adjacent microvilli (Fig. 1A). The intermicrovillar adhesion complex formed by these proteins is required for the uniform length and packing of microvilli and is remarkably homologous to the Usher syndrome complex found in two microvilli-like structures—the stereocilia of the inner ear and the calyceal processes of photoreceptors. In stereocilia, the Usher syndrome complex forms a link connecting the tip of one stereocilium to the side of its taller neighbor and is required for conveying force from the movement of stereocilia to stretch-activated channels at their tips (Fig. 1B). The stereociliary tip link is essential for the mechanotransduction underlying hearing, and mutations in the Usher syndrome complex are the leading cause of hereditary deaf-blindness. To investigate the much less-studied intermicrovillar adhesion complex, Choi et al. (4Choi M.S. Graves M.J. Matoo S. Storad Z.A. El Sheikh Idris R.A. Weck M.L. Smith Z.B. Tyska M.J. Crawley S.W. J. Biol. Chem. 2020; 295: 9281-9296Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar) developed a clever affinity purification strategy utilizing the extracellular domain of CDHR5 to pull down CDHR2 and other complex components. This affinity purification approach succeeded in pulling down known components of the intermicrovillar adhesion complex along with the calmodulin-like protein CALML4. Although calmodulin is a ubiquitous and intensively studied Ca2+-binding protein with hundreds of binding partners, little is known about CALML4 except that it is a member of the calmodulin superfamily. Choi et al. discovered that the major CALML4 transcript in human small intestine had not yet been documented and encodes a 153-amino acid isoform sharing ∼45% identity with the 149-amino acid sequence of calmodulin. Like calmodulin, CALML4 consists largely of four EF-hand motifs, but it is not yet clear whether each of CALML4’s EF-hands forms a functional binding site for a Ca2+ ion. To provide additional evidence that CALML4 is a bona fide component of the intermicrovillar adhesion complex, Choi et al. used immunofluorescence in intestine and cell culture models to show that endogenous CALM4 exhibits a striking localization to the tips of microvilli along with myosin-7b and other components complex. These results demonstrated CALML4’s location, but what is its function? A strong hint comes from the knowledge that in virtually all myosins the motor domain is followed by a light chain–binding domain consisting of one or more IQ motifs, each of which provides a binding site for a member of the calmodulin superfamily (5Heissler S.M. Sellers J.R. Myosin light chains: teaching old dogs new tricks.Bioarchitecture. 2014; 4 (26155737): 169-18810.1080/19490992.2015.1054092Crossref PubMed Scopus (54) Google Scholar). The IQ motifs in many myosins preferentially bind to calmodulin, but other IQ motifs bind to different members of the calmodulin superfamily, such as the essential and the regulatory light chains first identified in muscle myosin-2 (5Heissler S.M. Sellers J.R. Myosin light chains: teaching old dogs new tricks.Bioarchitecture. 2014; 4 (26155737): 169-18810.1080/19490992.2015.1054092Crossref PubMed Scopus (54) Google Scholar). Binding of the light chain stabilizes the myosin, enabling more efficient movements along its actin tracks. To test whether CALML4 can serve as a light chain for myosin-7b, Choi et al. showed that a construct consisting of the myosin-7b motor and light chain–binding domain was sufficient to pull down CALML4 and that myosin-7b’s five IQ motifs were necessary for the interaction. Importantly, pulldown experiments with myosin-7a constructs yielded similar results, suggesting that CALML4 can serve as a light chain for both myosin-7a and myosin-7b. Myosin-7b is hypothesized to transport itself and its binding partners to the microvillar tip (6Weck M.L. Crawley S.W. Stone C.R. Tyska M.J. Myosin-7b promotes distal tip localization of the intermicrovillar adhesion complex.Curr. Biol. 2016; 26 (27666969): 2717-272810.1016/j.cub.2016.08.014Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). To test this hypothesis, Choi et al. used myosin-7b knockdown in cell culture, along with a myosin-7b knockout mouse, to clearly demonstrate that CALML4 localization to tips requires myosin-7b. Conversely, CALML4 knockdown disrupted the tip localization of myosin-7b. CALM4 knockdown also disrupted the tip localization myosin-7b's binding partners in the intermicrovillar adhesion complex, and it inhibited the usual ability of microvilli to cluster together via their tips. These CALML4 knockdown results phenocopy those of myosin-7b knockdown, providing crucial evidence that myosin-7b's ability to transport and/or localize itself to microvillar tips is largely dependent on CALML4. In addition to revealing a new component of the intermicrovillar adhesion complex and a new light chain for myosin-7b, Choi et al. strongly suggest that CALML4 can serve as a light chain for myosin-7a, the intensively studied myosin at the core of the Usher syndrome complex. Previous research using baculovirus to co-express myosin-7a constructs consisting of the motor and light chain–binding domain with calmodulin reported only about three calmodulin molecules bound per heavy chain rather than the five light chains expected (7Sakai T. Jung H.S. Sato O. Yamada M.D. You D.J. Ikebe R. Ikebe M. Structure and regulation of the movement of human myosin VIIA.J. Biol. Chem. 2015; 290 (26001786): 17587-1759810.1074/jbc.M114.599365Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 8Haithcock J. Billington N. Choi K. Fordham J. Sellers J.R. Stafford W.F. White H. Forgacs E. The kinetic mechanism of mouse myosin VIIA.J. Biol. Chem. 2011; 286 (21212272): 8819-882810.1074/jbc.M110.163592Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar). These myosin-7a constructs also exhibited relatively low ATPase activities of less than ∼1 ATP/s/head, raising the possibility that their motor activity might be higher in the presence of a full complement of endogenous light chains. This makes it crucial to determine whether CALML4 is an endogenous light chain for myosin-7a and if its presence changes the level or regulation of motor activity. These results also highlight the importance of using proteomics approaches to identify the endogenous light chains for all other myosins whose endogenous light chains remain unclear (5Heissler S.M. Sellers J.R. Myosin light chains: teaching old dogs new tricks.Bioarchitecture. 2014; 4 (26155737): 169-18810.1080/19490992.2015.1054092Crossref PubMed Scopus (54) Google Scholar). It will also be important to determine which IQ motifs in the two mammalian myosin-7s bind to CALML4, if they preferentially bind to CALML4 as opposed to other members of the calmodulin superfamily, and if Ca2+ regulates their affinity (7Sakai T. Jung H.S. Sato O. Yamada M.D. You D.J. Ikebe R. Ikebe M. Structure and regulation of the movement of human myosin VIIA.J. Biol. Chem. 2015; 290 (26001786): 17587-1759810.1074/jbc.M114.599365Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Consistent with a role as a putative myosin-7a light chain, CALML4 is expressed in the inner ear and was recently identified in proteomic analyses of myosin-7a pulldowns (9Morgan C.P. Krey J.F. Grati M. Zhao B. Fallen S. Kannan-Sundhari A. Liu X.Z. Choi D. Müller U. Barr-Gillespie P.G. PDZD7-MYO7A complex identified in enriched stereocilia membranes.eLife. 2016; 5 (27525485): e1831210.7554/eLife.18312Crossref PubMed Scopus (23) Google Scholar). Most excitingly, as Choi et al. point out, the gene responsible for Usher syndrome type 1H remains unknown, and CALML4 is one of 27 genes identified within the USH1H candidate region (10Ahmed Z.M. Riazuddin S. Khan S.N. Friedman P.L. Riazuddin S. Friedman T.B. USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22-23.Clin. Genet. 2009; 75 (18505454): 86-9110.1111/j.1399-0004.2008.01038.xCrossref PubMed Scopus (34) Google Scholar). These results, together with the discoveries of Choi et al., make CALML4 a putative myosin-7a light chain and a candidate gene to underlie USH1H hereditary deaf-blindness. The small EF-hand protein CALML4 functions as a critical myosin light chain within the intermicrovillar adhesion complexJournal of Biological ChemistryVol. 295Issue 28PreviewSpecialized transporting and sensory epithelial cells employ homologous protocadherin-based adhesion complexes to remodel their apical membrane protrusions into organized functional arrays. Within the intestine, the nutrient-transporting enterocytes utilize the intermicrovillar adhesion complex (IMAC) to assemble their apical microvilli into an ordered brush border. The IMAC bears remarkable homology to the Usher complex, whose disruption results in the sensory disorder type 1 Usher syndrome (USH1). Full-Text PDF Open Access" @default.
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• W3041001808 title "A new light chain for myosin-7" @default.
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